Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors

ABSTRACT

Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of a co-pending applicationhaving U.S. Ser. No. 13/972,659, filed on Aug. 21, 2013, which is adivisional of application having U.S. Ser. No. 12/262,933, filed on Oct.31, 2008, now U.S. Pat. No. 8,541,429, which is a divisional ofapplication having U.S. Ser. No. 10/557,565, filed on Sep. 26, 2006, nowU.S. Pat. No. 7,482,354, which is a 371 of International applicationhaving Serial No. PCT/EP2004/050612, filed on Apr. 27, 2004, whichclaims benefit of U.S. Provisional Application No. 60/472,661, filed onMay 22, 2003, the entire content and disclosure of each of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pyrazolo-quinazoline derivatives, to aprocess for their preparation, to pharmaceutical compositions comprisingthem, and to their use as therapeutic agents, particularly in thetreatment of cancer and cell proliferation disorders.

2. Discussion of the Background

Several cytotoxic drugs such as, e.g., fluorouracil (5-FU), doxorubicinand camptothecins, damage DNA or affect cellular metabolic pathways andthus cause, in many cases, an indirect block of the cell cycle.Therefore, by producing an irreversible damage to both normal and tumorcells, these agents result in a significant toxicity and side-effects.

In this respect, compounds capable of functioning as highly specificantitumor agents by selectively leading to tumor cell arrest andapoptosis, with comparable efficacy but reduced toxicity than thecurrently available drugs, are desirable.

It is well known that progression through the cell cycle is governed bya series of checkpoint controls, otherwise referred to as restrictionpoints, which are regulated by a family of enzymes known as thecyclin-dependent kinases (cdk). In turn, the cdks themselves areregulated at many levels such as, for instance, binding to cyclins.

The coordinated activation and inactivation of different cyclin/cdkcomplexes is necessary for normal progression through the cell cycle.Both the critical G1-S and G2-M transitions are controlled by theactivation of different cyclin/cdk activities. In G1, both cyclin D/cdk4and cyclin E/cdk2 are thought to mediate the onset of S-phase.Progression through S-phase requires the activity of cyclin A/cdk2whereas the activation of cyclin A/cdc2 (cdk1) and cyclin B/cdc2 arerequired for the onset of mitosis. For a general reference to cyclinsand cyclin-dependent kinases see, for instance, Kevin R. Webster et al,in Exp. Opin. Invest. Drugs, 1998, Vol. 7(6), 865-887.

Checkpoint controls are defective in tumor cells due, in part, todisregulation of cdk activity. For example, altered expression of cyclinE and cdks has been observed in tumor cells, and deletion of the cdkinhibitor p27 KIP gene in mice has been shown to result in a higherincidence of cancer.

Increasing evidence supports the idea that the cdks are rate-limitingenzymes in cell cycle progression and, as such, rapresent moleculartargets for therapeutic intervention. In particular, the directinhibition of cdk/cyclin kinase activity should be helpful inrestricting the unregulated proliferation of a tumor cell.

Further protein kinases known in the art as being implicated in thegrowth of cancer cells are the Aurora kinases, in particular Aurora-2.

Aurora-2 was found to be over-expressed in a number of different tumortypes. Its gene locus maps at 20q13, a chromosomal region frequentlyamplified in many cancers, including breast [Cancer Res. 1999, 59(9)2041-4] and colon.

20q13 amplification correlates with poor prognosis in patients withnode-negative breast cancer and increased Aurora-2 expression isindicative of poor prognosis and decreased survival time in bladdercancer patients [J. Natl. Cancer Inst., 2002, 94(17) 1320-9]. For ageneral reference to Aurora-2 role in the abnormal centrosome functionin cancer see also Molecular Cancer Therapeutics, 2003, 2, 589-595.

SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds which are usefulin treating cell proliferative disorders caused by and/or associatedwith an altered protein kinase activity, for instance Aurora 2inhibitory activity and cell cycle dependent kinase activity. It isanother object to provide compounds which have protein kinase inhibitoryactivity.

The present inventors have now discovered that certainpyrazolo-quinazolines are endowed with protein kinase inhibitoryactivity and are thus useful in therapy as antitumor agents and lack, interms of both toxicity and side effects, the aforementioned drawbacksassociated with currently available antitumor drugs.

More specifically, the pyrazolo-quinazolines of the invention are usefulin the treatment of a variety of cancers including, but not limited to:carcinoma such as bladder, breast, colon, kidney, liver, lung, includingsmall cell lung cancer, esophagus, gall-bladder, ovary, pancreas,stomach, cervix, thyroid, prostate, and skin, including squamous cellcarcinoma; hematopoietic tumors of lymphoid lineage including leukaemia,acute lymphocitic leukaemia, acute lymphoblastic leukaemia, B-celllymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors ofmyeloid lineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytomaneuroblastoma, glioma and schwannomas; other tumors, including melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Due to the key role of cell cycle kinases such as Aurora or cdks in theregulation of cellular proliferation, these pyrazolo-quinazolinederivatives are also useful in the treatment of a variety of cellproliferative disorders such as, for example, benign prostatehyperplasia, familial adenomatosis, polyposis, neurofibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis andpost-surgical stenosis and restenosis.

The compounds of the invention may be useful in treatment of Alzheimer'sdisease, as suggested by the fact that cdk5 is involved in thephosphorylation of tau protein (J. Biochem. 117, 741-749, 1995).

The compounds of this invention, as modulators of apoptosis, may also beuseful in the treatment of cancer, viral infections, prevention of AIDSdevelopment in HIV-infected individuals, autoimmune diseases andneurodegenerative disorders.

The compounds of this invention may be useful in inhibiting tumorangiogenesis and metastasis, as well as in the treatment of organtransplant rejection and host versus graft disease.

The compounds of the invention may also act as inhibitor of otherprotein kinases, e.g., protein kinase C in different isoforms, Met,PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Bub-1, PLK, Chk1, Chk2, HER2, raf1,MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, PI3K, weel kinase, Src, Abl,Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, and thus be effective in thetreatment of diseases associated with other protein kinases.

The compounds of the invention are also useful in the treatment andprevention of radiotherapy-induced or chemotherapy-induced alopecia.

Accordingly, in a first embodiment, the present invention provides amethod for treating cell proliferative disorders caused by and/orassociated with an altered protein kinase activity, like for instanceAurora 2 activity and cell cycle dependent kinase activity, byadministering to a mammal in need thereof an effective amount of apyrazolo-quinazoline derivative represented by formula (Ia) or (Ib)

wherein

R is hydrogen or an optionally substituted group selected from amino,straight or branched C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, cycloalkyl-alkyl,aryl, arylalkyl, heterocyclyl or heterocyclylalkyl;

X is a single bond or a divalent radical selected from —NR′—, —CONR′—,—NH—CO—NH—, —O—, —S— or —SO₂—, wherein R′ is hydrogen or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl or, together with the nitrogen atom to which they arebonded, R and R′ may form a 5 to 6 membered heteroaryl or heterocyclylgroup optionally containing one additional heteroatom selected among N,O or S;

R₁, bonded to any one of the nitrogen atoms of the pyrazole ring as performulae (Ia) or (Ib), represents a hydrogen atom or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, informula (Ib), R₁ is a divalent —(CH₂)_(n)—NH— group being linked to R₂,wherein n is 2 or 3;

R₂ is a group selected from —NR″R′″, —N(OH)R″, —OR″ or —R″, wherein R″and R′″ are, each independently, hydrogen or an optionally substitutedgroup selected from straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkylor cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkylor, together with the nitrogen atom to which they are bonded, R″ and R′″may form a 5 to 6 membered heteroaryl or heterocyclyl group, optionallycontaining one additional heteroatom selected among N, O or S;

A is a divalent group selected from —CH₂—, —(CH₂)₂—, —CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂— or —CH═CH—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention also provides a method fortreating cell proliferative disorders caused by and/or associated withan altered protein kinase activity, like cell cycle dependent kinaseactivity, by administering to a mammal in need thereof an effectiveamount of a pyrazolo-quinazoline derivative represented by the aboveformula (Ia) or (Ib).

In a preferred embodiment of the methods described above, the cellproliferative disorder is selected from the group consisting of cancer,Alzheimer's disease, viral infections, auto-immune diseases andneurodegenerative disorders.

Specific types of cancer that may be treated include carcinoma, squamouscell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage,tumors of mesenchymal origin, tumors of the central and peripheralnervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma,xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, andKaposi's sarcoma.

In another preferred embodiment of the method described above, the cellproliferative disorder is selected from the group consisting of benignprostate hyperplasia, familial adenomatosis, polyposis,neuro-fibromatosis, psoriasis, vascular smooth cell proliferationassociated with atherosclerosis, pulmonary fibrosis, arthritis,glomerulonephritis and post-surgical stenosis and restenosis. Inaddition, the inventive method provides tumor angiogenesis andmetastasis inhibition as well as treatment of organ transplant rejectionand host versus graft disease. The inventive methods may also providecell cycle inhibition or cdk/cyclin dependent inhibition.

In addition to the above, the methods object of the present inventionprovide treatment and prevention of radiotherapy-induced orchemotherapy-induced alopecia.

The present invention also provides a pyrazolo-quinazoline derivativerepresented by formula (Ia) or (Ib)

wherein

R is hydrogen or an optionally substituted group selected from amino,straight or branched C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, cycloalkyl-alkyl,aryl, arylalkyl, heterocyclyl or heterocyclylalkyl;

X is a single bond or a divalent radical selected from —NR′—, —CONR′—,—NH—CO—NH—, —O—, —S— or —SO₂—, wherein R′ is hydrogen or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl or, together with the nitrogen atom to which they arebonded, R and R′ may form a 5 to 6 membered heteroaryl or heterocyclylgroup optionally containing one additional heteroatom selected among N,O or S;

R₁, bonded to any one of the nitrogen atoms of the pyrazole ring as performulae (Ia) or (Ib), represents a hydrogen atom or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, informula (Ib), R₁ is a divalent —(CH₂)_(n)—NH— group being linked to R₂,wherein n is 2 or 3;

R₂ is a group selected from —NR″R′″, —N(OH)R″, —OR″ or —R″, wherein R″and R′″ are, each independently, hydrogen or an optionally substitutedgroup selected from straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkylor cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkylor, together with the nitrogen atom to which they are bonded, R″ and R″may form a 5 to 6 membered heteroaryl or heterocyclyl group, optionallycontaining one additional heteroatom selected among N, O or S;

A is a divalent group selected from —CH₂—, —(CH₂)₂—, —CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂— or —CH═CH—;

or a pharmaceutically acceptable salt thereof.

The present invention also includes methods of synthesizing thepyrazolo-quinazoline derivatives represented by formulae (Ia) or (Ib)that, unless otherwise provided, may be conveniently grouped and definedas compounds of formula (I). Pharmaceutical compositions comprising thepyrazolo-quinazoline derivatives of formula (I) are also included in thepresent invention.

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Several heterocyclic compounds are known in the art as protein kinaseinhibitors. As an example, 2-carboxamido-pyrazoles and2-ureido-pyrazoles, and derivatives thereof, have been disclosed asprotein kinase inhibitors in the international patent applications WO01/12189, WO 01/12188, WO 02/48114 and WO 02/70515, all in the name ofthe applicant itself.

Fused bicyclic compounds comprising pyrazole moieties and possessingkinase inhibitory activity have been also disclosed in WO 00/69846, WO02/12242 as well as WO 03/028720 and still unpublished U.S. patentapplication 60/381,092 (filed in May 17, 2002), all in the name of theapplicant itself.

Fused tricyclic derivatives possessing kinase inhibitory activity arealso disclosed in two copending applications PCT/EP03/01594 andPCT/US03/04844 (both claiming Feb. 19, 2002 priority from USapplications No. 60/357,918 and No. 60/357,960, respectively) andherewith incorporated by reference; none of the said applicationsspecifically disclose the derivatives in re.

In addition, fused polycyclic pyrimidine derivatives as protein kinaseinhibitors are also disclosed in the international patent applicationsWO 98/58926 and WO 98/28281, both in the name of Celltech TherapeuticsLtd; though comprised within the general formula of both applications,no specific examples of pyrazolo-quinazolines of the present inventionare exemplified therein.

Finally, heterocyclic ring fused pyrimidine derivatives for thetreatment of hyperproliferative diseases are disclosed in WO 96/40142 inthe name of Pfizer Inc.

The compounds of formula (I) of the invention may have asymmetric carbonatoms and may therefore exist as individual optical isomers, as racemicadmixtures or as any other admixture comprising a majority of one of thetwo optical isomers, which are all to be intended as within the scope ofthe present invention.

Likewise, the use as an antitumor agent of all the possible isomers andtheir admixtures and of both the metabolites and the pharmaceuticallyacceptable bio-precursors (otherwise referred to as pro-drugs) of thecompounds of formula (I) are also within the scope of the presentinvention.

Prodrugs are any covalently bonded compounds which release the activeparent drug, according to formula (I), in vivo.

In cases when compounds may exist in tautomeric forms, for instanceketo-enol tautomers, each tautomeric form is contemplated as beingincluded within this invention whether existing in equilibrium orpredominantly in one form.

In the present description, unless otherwise specified, with the termstraight or branched C₁-C₆ alkyl we intend any of the groups such as,for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

With the term C₃-C₁₀ cycloalkyl we intend, unless otherwise provided, acycloaliphatic ring such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, as well as any bridged cycloalkyl group with up to 10 carbonatoms.

The term aryl includes carbocyclic or heterocyclic hydrocarbons withfrom 1 to 2 ring moieties, either fused or linked to each other bysingle bonds, wherein at least one of the rings is aromatic; if present,any aromatic heterocyclic hydrocarbon also referred to as heteroarylgroup, comprises a 5 to 6 membered ring with from 1 to 3 heteroatomsselected among N, O or S.

Examples of aryl groups according to the invention are, for instance,phenyl, biphenyl, α- or β-naphthyl, dihydronaphthyl, thienyl,benzothienyl, furyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, purinyl, quinolyl,isoquinolyl, dihydroquinolinyl, quinoxalinyl, benzodioxolyl, indanyl,indenyl, triazolyl, and the like.

Unless otherwise specified, the term heterocyclyl includes 5 to 6membered saturated, partly unsaturated or fully unsaturated heterocycleswith from 1 to 3 heteroatoms selected among N, O or S. Apart from thefully unsaturated heterocycles, previously referred to as aromaticheterocycles and encompassed by the term aryl, examples of saturated orpartly unsaturated heterocycles according to the invention are, forinstance, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine,pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran,tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine andthe like.

From all of the above, it is clear to the skilled man that any compoundof the invention wherein X represents a single bond has to be intendedas having the R group directly linked to the pyrimidine moiety.

According to the above indicated substituent meanings and unlessotherwise specified, any of the above R, R′, R₁, R″ and R′″ group may beoptionally substituted in any of their free positions by one or moregroups, for instance 1 to 6 groups, independently selected from:halogen, nitro, oxo groups (═O), cyano, azido, alkyl, polyfluorinatedalkyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,cycloalkyl, alkylaryl, alkylheterocyclyl, hydroxy, alkoxy,polyfluorinated alkoxy, aryloxy, arylalkyloxy, heterocyclyloxy,heterocyclylalkyloxy, methylenedioxy, alkylcarbonyloxy,alkylcarbonyloxyalkyl, arylcarbonyloxy, carboxy, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino,aminoalkyl, alkylaminoalkyl, alkylaminoalkyloxy, ureido, alkylamino,dialkylamino, arylamino, diarylamino, formylamino, alkylcarbonylamino,arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino,alkoxyimino, alkylsulfonylamino, arylsulfonylamino, formyl,alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, alkylsulfonyl, arylsulfonyl,heterocyclylsulfonyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, arylthio and alkylthio.

In this respect, with the term halogen atom we intend a fluorine,chlorine, bromine or iodine atom.

With the term perfluorinated alkyl we intend any of the above straightor branched C₁-C₆ alkyl groups which are substituted by more than onefluorine atom such as, for instance, trifluoromethyl, trifluoroethyl,1,1,1,3,3,3-hexafluoropropyl, and the like.

With the term alkoxy, aryloxy, heterocyclyloxy and derivatives thereof,e.g. perfluorinated alkoxy, we intend any of the above alkyl, aryl orheterocyclyl groups linked to the rest of the molecule through an oxygenatom (—O—).

From all of the above, it is clear to the skilled person that any groupwhich name is a composite name such as, for instance, arylalkyl orheterocyclylalkyl has to be intended as conventionally construed by theparts from which it derives, e.g. by an alkyl group which is furthersubstituted by aryl or heterocyclyl, wherein alkyl, aryl or heterocyclylare as above defined.

Likewise, any of the terms such as, for instance, alkylthio, alkylamino,dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl,heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like, includegroups wherein the alkyl, alkoxy, aryl, cycloalkyl and heterocyclylmoieties are as above defined.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition salts with inorganic or organic acids, e.g.,nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric,acetic, trifluoroacetic propionic, glycolic, lactic, oxalic, malonic,malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic,methanesulphonic, isethionic and salicylic acid, as well as the saltswith inorganic or organic bases, e.g., alkali or alkaline-earth metals,especially sodium, potassium, calcium or magnesium hydroxides,carbonates or bicarbonates, acyclic or cyclic amines, preferablymethylamine, ethylamine, diethylamine, triethylamine, piperidine and thelike.

According to a first embodiment of the invention addressed to thecompounds of formula (Ia) or (Ib), preferred derivatives are thosewherein X is a group —NH— and R₂ is a group selected from —NHR″,—N(OH)R″, —OR″ or —R″, wherein R″ is an optionally substituted groupselected from C₃-C₆ cycloalkyl or cycloalkyl-alkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl; and R, R₁ and A are as above defined.

Also preferred are the compounds of formula (Ia) or (Ib) wherein X is agroup —O— and R₂ is a group selected from —NHR″, —N(OH)R″, —OR″ or —R″,wherein R″ is an optionally substituted group selected from C₃-C₆cycloalkyl or cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl; and R, R₁ and A are as above defined.

Also preferred are the compounds of formula (Ia) or (Ib) wherein X is agroup —S— and R₂ is a group selected from —NHR″, —N(OH)R″, —OR″ or —R″,wherein R″ is an optionally substituted group selected from C₃-C₆cycloalkyl or cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl; and R, R₁ and A are as above defined.

Even more preferred, within the above classes of compounds (Ia) or (Ib)are those same derivatives wherein A is a group —(CH₂)₂—.

According to another embodiment of the invention addressed to thecompounds of formula (Ia) or (Ib), a class of preferred compounds isrepresented by those derivatives wherein X is a group —NH— and R₂ is agroup —NHR″ or —N(OH)R″ wherein R″ is a hydrogen atom or a straight orbranched C₁-C₄ alkyl group; and wherein A, R and R₁ are as abovedefined.

Another class of preferred compounds of the invention of formula (Ia) or(Ib) is represented by the derivatives wherein X is a group —O— and R₂is a group —NHR″ or —N(OH)R″ wherein R″ is a hydrogen atom or a straightor branched C₁-C₄ alkyl group; and wherein A, R and R₁ are as abovedefined.

Another class of preferred compounds of the invention of formula (Ia) or(Ib) is represented by the derivatives wherein X is a group —S— and R₂is a group —NHR″ or —N(OH)R″ wherein R″ is a hydrogen atom or a straightor branched C₁-C₄ alkyl group; and wherein A, R and R₁ are as abovedefined.

Another class of preferred compounds of the invention of formula (Ib) isrepresented by the derivatives wherein R, X and A are as above definedand R₁ and R₂ are linked together through a divalent —(CH₂)_(n)—NH—group so as to give rise to:

Also preferred, within the above class of derivatives of formula (Ia)and (Ib), are the compounds wherein A is a group selected from—CH₂—C(CH₃)₂— or C(CH₃)₂—CH₂—.

For a reference to any specific compound of formula (Ia) or (Ib) of theinvention, optionally in the form of a pharmaceutically acceptable salt,see the experimental section and claims.

As formerly indicated, a further object of the present invention isrepresented by the process for preparing the compounds of formula (I)which formula, unless otherwise specifically provided, has to beintended as comprising the derivatives of formula (Ia) and (Tb).

Therefore, the compounds of formula (I) or the pharmaceuticallyacceptable salts thereof may be obtained by a process comprising:

(1) when A is a —(CH₂)₂— group:

st.1) reacting 2-ethoxy-2-cyclohexen-1-one with diethyl oxalate, in thepresence of lithium (bis-trimethylsilyl)amide [LiN(TMS)₂], so as toobtain a compound of formula (II)

and treating it with a hydrazine derivative of formula (III)R₁—NHNH₂  (III)wherein R₁ has the above reported meanings, according to the operativeconditions set forth in any one of the steps (st.2a), (st.2b) or (st.2c)

st.2a) in the presence of a lower alcohol so as to obtain a mixture ofthe compounds of formula (IVa) and (IVb)

wherein R₁ is as above reported, and separating their mixture into thesingle compounds (IVa) and (IVb);

st.2b) in the presence of acetic acid so as to obtain a compound offormula (IVa);

st.2c) by alkylating a compound of formula (IVa) being obtained in step(st.2a) or (st.2b) and wherein R₁ is hydrogen with the compounds offormula (IVc)R₁Y  (IVc)wherein Y is a suitable leaving group such as mesyl, tosyl, halogen, asto obtain a mixture of compounds of formula (IVa) and (IVb) wherein R₁is as above reported and separating their mixture into the compounds(IVa) and (IVb);

st.3) reacting the compound of formula (IVa) prepared according to anyone of steps (st.2a), (st.2b) or (st.2c), or of formula (IVb) preparedaccording to steps (st.2a) or (st.2c), withdimethylformamide-di-tert-butylacetale so as to obtain a compound offormula (Va) or (Vb)

wherein R₁ is as above reported; and reacting the compound of formula(Va) or (Vb) according to any one of the alternative steps (st.4a),(st.4b) or (st.4c)

st.4a) with guanidine so as to obtain a compound of formula (Ia) or (Ib)

wherein R—X— is amino, R₂ is ethoxy, and R₁ is as above defined; andoptionally converting them into other derivatives of formula (I);

st.4b) with a guanidine derivative of formula (VI)R—NH—C(═NH)NH₂  (VI)wherein R is as above reported, so as to obtain a compound of formula(Ia) or (Ib) wherein R and R₁ are as above reported, X is —NH—, and R₂is ethoxy; and optionally converting them into other derivatives offormula (I);

st.4c) with an alkylisothiourea of formula (VII)R—S—C(═NH)NH₂  (VII)wherein R is as above reported, so as to obtain a compound of formula(Ia) or (Ib) wherein R and R₁ are as above reported, X is —S— and R₂ isethoxy; and optionally converting them into other derivatives of formula(I);

st.4d) with methylisourea so as to obtain a compound of formula (Ia) or(Ib) wherein R₁ is as above reported R is methyl, X is —O— and R₂ isethoxy; and optionally converting them into other derivatives of formula(I);

(2) when A is a —C(CH₃)₂—CH₂— group:

st.5) reacting 2-methoxy-4,4-dimethyl-2-cyclohexen-1-one with diethyloxalate, in the presence of [LiN(TMS)₂], so as to obtain a compound offormula (VIII)

st.6) reacting the compound of formula (VIII) with a hydrazinederivative of formula (III) according to any one of previous steps(st.2a) or (st.2b) so as to obtain the compound of formula (IXa) or(IXb)

wherein R₁ is as above reported;

st.7) reacting the compound of formula (IXa) or (IXb) with ethyl formateunder basic conditions, so as to obtain the compound of formula (Xa) or(Xb)

st.8) reacting the compound of formula (Xa) or (Xb) with guanidine or aguanidine derivative of formula (VI), so as to obtain a compound offormula (Ia) or (Ib)

wherein R and R₁ are as above reported, X is —NH—, and R₂ is ethoxy; andoptionally to converting them into other derivatives of formula (I);

(3) when A is a —CH₂—C(CH₃)₂— group:

st.9) reacting 2-methoxy-5,5-dimethyl-2-cyclohexen-1-one with diethyloxalate in the presence of sodium hydride, so as to obtain the compoundof formula (XI)

st.10) reacting the compound of formula (XI) with a hydrazine derivativeof formula (III) according to any one of previous steps (st.2a) or(st.2b) so as to obtain the compound of formula (XIIa) or (XIIb)

wherein R₁ is as above reported;

st.11) reacting the compound of formula (XIIa) or (XIIb) withdimethylformamide-di-tert-butylacetale so as to obtain a compound offormula (XIIIa) or (XIIIb)

st.12) reacting the compound of formula (XIIIa) or (XIIIb) withguanidine or a guanidine derivative of formula (VI), so as to obtain acompound of formula (Ia) or (Ib)

wherein R and R₁ are as above reported, X is —NH—, and R₂ is ethoxy; andoptionally converting them into other derivatives of formula (I);

(4) when, in formula (Ib), A is a —(CH₂)₂— group, —CH₂—C(CH₃)₂— group,—C(CH₃)₂—CH₂— group, R₁ is directly linked to R₂ so as to yield atetra-cyclic ring structure:

st.13) reacting a compound of formula (IV), (IX), (XII) wherein R₁ ishydrogen, obtained according to (st.2), (st.6), (st.10) of the process,with triphenylmethyl chloride so as to obtain a compound of formula(XIV)

wherein Tr stands for trityl (triphenylmethyl);

st.14) reacting the compound of formula (XIV) withdimethylformamide-di-tert-butylacetale, as set forth in step (st.3), soas to obtain a compound of formula (XV)

st.15) reacting the compound of formula (XV) with a suitable guanidinederivative of formula (VI), as set forth in step (st.4b), so as toobtain a compound of formula (Ia) or (Ib)

wherein R is as above defined, A is a —(CH₂)₂— group, —CH₂—C(CH₃)₂—group, —C(CH₃)₂—CH₂— group, X is NH, R₁ is trityl and R₂ is ethoxy;

st.16) reacting the above compound of formula (Ia) or (Ib) under acidicconditions, so as to obtain the corresponding compound of formula (Ia)or (Ib) wherein R₁ is hydrogen;

st.17) reacting the above compound of formula (Ia) or (Ib) with asuitable alkylating agent of formula (XVI) in the presence of lithiumtert-butylateBr—(CH₂)_(n)—NH—BOC  (XVI)wherein n is 2 or 3, so as to obtain a compound of formula (Ib)

wherein A, n and R are as above defined;

st.18) reacting the above compound of formula (Ib) under acidicconditions, so as to convert the tert-butoxycarbonylamino group intoamino (deprotection) and reacting it with cesium carbonate (CsCO₃) so asto obtain any one of the two compounds of formula (Ib)

wherein A and R is as above defined, and optionally converting them intoother derivatives of formula (I);

(5) when R₂ is a bulky group:

st.19) reacting 2-ethoxy-2-cyclohexenone withdimethylformamide-di-tert-butylacetale, as reported in step (st.3), soas to obtain a compound of formula (XVII)

st.20) reacting the compound of formula (XVII) with a derivative offormula (VII), according to step (st.4c), so as to obtain a compound offormula (XVIII)

wherein R is as above defined; and subsequently treating it under acidicconditions so as to obtain a compound of formula (XIX)

st.21) reacting the compound of formula (XIX) with a compound of formula(XX)

wherein R₂ is a bulky group, so as to obtain a compound of formula (XXI)

st.22) reacting the compound of formula (XXI) with a hydrazinederivative of formula (III), as per step (st.1) of the process, so as toobtain a compound of formula (I) wherein R and R₁ are as above defined,X is —S— and R₂ is a bulky group; and optionally converting them intoother derivatives of formula (I).

As above reported, the compounds of formula (I) which are preparedaccording to the process object of the invention, for instance as setforth in steps (st.4a), (st.4b), (st.4c), (st.8), (st.12), (st.13),(st.18) and (st.22), can be conveniently converted into other compoundsof formula (I) by operating according to well-known operativeconditions.

As an example, the compounds of formula (I):

st.23) wherein R₂ is ethoxy may be converted into the compounds offormula (Ia) or (Ib) wherein R₂ is amino by treatment with ammoniumhydroxide

st.24) wherein R₂ is ethoxy may be converted into the compounds offormula (I) wherein R₂ is a group —NHR″ by treatment with an amine offormula R″—NH (XXII)

st.25) wherein R₂ is ethoxy may be converted into the compounds offormula (I) wherein R₂ is a group —OH through acidic or basic hydrolysis

st.26) wherein R₂ is —OH may be converted into the compounds of formula(I) wherein R₂ is a group —NR″R′″ or —N(OH)R″, through reaction with aderivative of formula (XXIII) or (XXIV)R″R′″NH  (XXIII)R″NHOH  (XXIV)under basic conditions and in the presence of a suitable condensingagent

st.27) wherein R is hydrogen and X is —NH— may be converted into thecompounds of formula (I) wherein R is other than hydrogen, as abovedefined, and X is —CONH—, through reaction with an acid halide, forinstance chloride, of formula R—COCl (XXV)

st.28) wherein R is hydrogen and X is —NH— may be converted into thecompounds of formula (I) wherein R is other than hydrogen, as abovedefined, and X is —NH—CO—NH—, through reaction with an isocyanate offormula R—NCO (XXVI)

st.29) wherein R is hydrogen and X is —NH— may be converted into thecompounds of formula (I) wherein R is aryl and X is —NH—, by firstconverting the amino group to iodine with iso-amylnitrite anddiiodomethane or cesium iodide, in the presence of iodine and CuI, andby subsequently reacting the iododerivative with an arylamine of formulaR—NH₂ (XXVII), in the presence of palladium acetate and(2,2′-bis(diphenylphosphino))-1,1′-binaphthalene (BINAP)

st.29a) wherein R is hydrogen and X is —NH— may be converted into thecompounds of formula (I) wherein R is alkyl, cycloalkyl,cycloalkyl-alkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, and X is—NH—, by first converting the amino group to iodine, as described in theprevious step (st.29), and by subsequently reacting the iododerivativewith an alkyl, cycloalkyl, cycloalkyl-alkyl, arylalkyl, heterocyclyl orheterocyclylalkyl amine of formula RNH₂ (XXVII), wherein R is as thereindefined;

st.30) wherein R is hydrogen and X is —NH— may be converted into thecompounds of formula (I) wherein R is aryl and X is a single bond, byfirst converting the amino group to iodine, as per the above step(st.29), and by subsequently reacting the iododerivative with anarylboronic acid of formula R—B(OH)₂ (XXVIII), in the presence of apalladium derivative

st.31) wherein R is hydrogen and X is —NH— may be converted into thecompounds of formula (I) wherein R is alkyl or arylmethyl, by reactionwith an alkyl aldehyde or aryl-aldehyde of formula R—CHO (XXIX) in thepresence of sodium cyanoborohydride (NaBH₃CN) and acetic acid

st.31a) wherein R is hydrogen and X is —NH— may be converted into thecompounds of formula (I) wherein R is cycloalkyl or heterocycloalkyl, byreaction with an cycloalkyl ketone or heterocycloalkylketone in thepresence of sodium triacetoxyborohydride (NaBH(OAc)₃) andtrifluoroacetic acid

st.32) wherein R is as above defined, e.g. methyl, and X is —S— may beconverted into the compounds of formula (I) wherein R is an optionallysubstituted alkyl, cycloalkyl, heterocyclyl, cycloalkyl-alkyl, arylalkylor heterocyclylalkyl group, by first converting the RS— group into RSO₂—under oxidative conditions, and by then reacting the sulfonyl derivativewith an amine of formula R—NH₂ (XXVII) wherein R is an optionallysubstituted alkyl, cycloalkyl, heterocyclyl, cycloalkyl-alkyl, arylalkylor heterocyclylalkyl group

st.33) wherein R is as above defined, e.g. methyl, and X is —S— may beconverted into the compounds of formula (I) wherein R is as defined informula (I) and X is —O—, by first converting the RS— group into RSO₂—as per step (st.32) and by then reacting the sulfonyl derivative with acompound of formula R—OH (XXX)

st.33a) wherein R is methyl, and X is —O— may be converted into thecompounds of formula (I) wherein R is as defined in formula (I) and X is—O—, by first converting the MeO— group into HO—, then by reacting itwith a triflating agent so as to obtain the correspondingtrifluoromethansulfonate and finally by reacting it with a compound offormula R—OH (XXX)

st.33b) wherein R is methyl and X is —O— may be converted into thecompounds of formula (I) wherein R is an optionally substituted alkyl,cycloalkyl, heterocyclyl, cycloalkyl-alkyl, heterocyclylalkyl group, andX is —NH—, by first converting the MeO— group into HO—, then by reactingit with a triflating agent so as to obtain the correspondingtrifluoromethansulfonate and finally by reacting it with an amine offormula R—NH₂ (XXVII) wherein R is an optionally substituted alkyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, arylalkyl orheterocyclylalkyl group

st. 33c) wherein R is methyl and X is —O— may be converted into thecompounds of formula (I) wherein R is an aryl and X is —NH—, by firstconverting the MeO— group into —OH, then by reacting it with atriflating agent so as to obtain the correspondingtrifluoromethansulfonate and finally by reacting it with an amine offormula RNH₂ (XXVII) wherein R is an optionally substituted aryl in thepresence of palladium acetate and BINAP;

st.34) wherein A is a —(CH₂)₂— group may be converted into the compoundsof formula (I) wherein A is a —CH—CH— group, under dehydrogenatingoperative conditions in the presence of a Pd or Pt catalyst.

The above process, in any one of the aforementioned variants, is ananalogy process which can be carried out according to well known methodsknown in the art.

According to steps (st.1) of the process, 2-ethoxy-2-cyclohexen-1-one isreacted with diethyl oxalate in the presence of LiN(TMS)₂ and of asuitable solvent such as, for instance, dioxane, tetrahydrofuran ordiethyl ether.

According to step (st.2a), the compound of formula (II) is reacted witha suitable hydrazine derivative of formula (III), in the presence of alower alcohol such as methanol, ethanol or admixtures thereof.Preferably, the above reaction is carried out in ethanol at refluxingtemperature, so as to obtain a mixture of both compounds of formula(IVa) and (IVb) wherein the former is present in major amounts. Theirseparation into the single compounds (IVa) and (IVb) is carried outunder conventional methods, for instance through preparative HPLC.

By working according to step (st.2b) of the process, instead, that is byreacting the compound of formula (II) with the hydrazine derivative offormula (III) in the presence of acetic acid, a single compound offormula (IVa) is obtained. The reaction is preferably carried out atroom temperature.

According to step (st.2c) of the process, the compound of formula (IVa)wherein R₁ is hydrogen, is reacted with a suitable compound of formula(IVc) in the presence of a base such as sodium hydride in a suitablesolvent, for instance tetrahydrofuran, dioxane or dimethylformamide, ata temperature ranging from room temperature to 100° C., so as to obtaina mixture of compounds (IVa) and (IVb) wherein the former is present inmajor amounts, and by separating them under conventional methods, forinstance through preparative HPLC.

According to step (st.3) of the process, the compound of formula (IVa)or (IVb) is reacted with dimethylformamide-di-tert-butylacetale, in thepresence of a suitable solvent such as, for instance, dimethylformamide,so as to get the compounds of formula (Va) or (Vb), respectively.Preferably, the reaction is carried out at a temperature ranging fromroom temperature to about 70° C.

According to any one of the alternative steps (st.4a), (st.4b), (st.4c)or (st.4d) of the process, the compound of formula (Va) or (Vb) isreacted with guanidine, guanidine salts or derivatives thereof,alkylisothiourea or methylisourea so as to obtain the correspondingcompound of formula (Ia) or (Ib) through pyrimidine ring formation. Anyof the above reactions is carried out according to conventional methods.As an example, the reactions with guanidine or salts thereof such ashydrochloride, carbonate or nitrate, or with the guanidine derivative offormula (VI), as set forth in steps (st.4a) or (st.4b), are carried outin a lower alcoholic solvent under neutral or basic conditions,preferably with ethanol and sodium ethylate or with diazabicycloundecene(DBU) at refluxing temperature or, alternatively, in dimethylformamideat a temperature ranging from 80° C. to refluxing temperature in thepresence of potassium carbonate. The reaction with alkylisothiourea(VII), in (st.4c), is carried out in the presence of potassium acetateand in a suitable solvent such as dimethylformamide at refluxingtemperature.

The reaction with methylisourea (st.4d) is carried out in a suitablesolvent such as acetonitrile and in the presence of a base such aspotassium carbonate at refluxing temperature.

The reactions of steps (st.5) and (st.6) are carried out under theoperative conditions set forth in steps (st.1), (st.2a) or (st.2b) andlead to the desired compounds of formula (IXa) or (IXb), respectively.

Step (st.7) of the process is preferably carried out by reacting thederivative of formula (IXa) or (IXb) with ethyl formate under basicconditions, preferably in the presence of sodium ethylate or sodiumhydride and of a suitable solvent such as, for instance, diethyl ether,tetrahydrofuran or dioxane, at a temperature ranging from roomtemperature to refluxing temperature.

The reaction conditions of step (st.8) are those previously reported forsteps (st.4a and st.4b).

According to step (st.9), 2-methoxy-5,5-dimethyl-2-cyclohexen-1-one isreacted with diethyl oxalate in the presence of sodium hydride and in asuitable solvent such as diethyl ether, tetrahydrofuran or dioxane, atrefluxing temperature.

The subsequent reaction conditions of steps (st.10) are essentiallythose previously reported for steps (st.2a) or (st.2b), and those ofsteps (st.11) and (st.12) correspond to those of (st.3) and (st.4a andst.4b), respectively.

According to step (st.13) of the process, it is clear to the skilled manthat both compounds of formula (IVa) or (IVb) wherein R₁ is a hydrogenatom are tautomeric forms of a given compound which can be convenientlyidentified as having formula (IV). In this respect, this same derivativeis reacted with triphenylmethyl chloride so as to obtain a compound offormula (XIV) wherein either one of the two pyrazole nitrogen atoms arealkylated with a trityl (e.g. triphenylmethyl) group.

The operative conditions in steps (st.14) and (st.15) of the processessentially correspond to those already reported for steps (st.3) and(st.4a and st.4b). According to step (st.16), the trityl group of thecompounds of formula (I) is removed under acidic conditions, forinstance with trifluoroacetic acid and in the presence of a suitablesolvent such as dichloromethane, so as to give rise to the correspondingcompound of formula (I) wherein R₁ is hydrogen, in both forms:

Its subsequent alkylation with a derivative of formula (XVI), accordingto step (st.17) of the process, allows to selectively alkylate thepyrazole nitrogen atom which is in proximity of the —COOEt group; thisreaction may be carried out with lithium tert-butylate and in a suitablesolvent, such as dioxane, diethyl ether or tetrahydrofuran.

According to step (st.18), the above compound is first converted intothe free amino derivative by working according to conventional methods,for instance under acidic conditions, preferably with hydrochloric acid,in a suitable solvent such as dioxane at refluxing temperature, andsubsequently cyclised to the desired tetracyclic derivative in thepresence of a base such as cesium carbonate (CsCO₃) and in a suitablesolvent such as a lower alcohol, preferably methanol, ranging from roomtemperature to reflux.

The operative conditions of steps (st.19) and (st.20) of the processessentially correspond to those already reported for steps (st.3) and(st.4c); the subsequent acidic treatment of the compound of formula(XVIII) to the compound of formula (XIX) is preferably carried out withan aqueous solution of acetic acid, at a temperature of about 100° C.

According to step (st.21), the compound of formula (XIX) is reacted witha suitable derivative of formula (XX) in the presence of sodium hydrideand in a suitable solvent, e.g. diethyl ether, tetrahydrofuran ordioxane, at a temperature ranging from about −50° C. to roomtemperature.

The operative conditions of step (st.22) essentially correspond to thoseof step (st.1) of the process.

As formerly indicated, the compounds of formula (I) thus prepared may beeasily converted into several other compounds of formula (I) of theinvention.

As an example, compounds of formula (I) bearing R₂ as an ethoxy group,or even as an alkoxy group, can be converted into a variety ofderivatives according to methods well-known in the art to convertcarboxyester groups (—COOR₂) into carboxamides (—CONH₂), N-substitutedcarboxamides (—CONHR″) and carboxylic acids (—COOH), for instance asreported in steps (st.23), (st.24) and (st.25).

The operative conditions are those widely known in the art and maycomprise, for instance in the conversion of a carboxyester group into acarboxamide group, the reaction with ammonia or ammonium hydroxide inthe presence of a suitable solvent such as a lower alcohol,dimethylformamide or mixtures thereof; preferably the reaction iscarried out with ammonium hydroxide in a methanol/dimethylformamidemixture, at a temperature ranging from about 50° C. to about 100° C.

Analogous operative conditions apply in the preparation of N-substitutedcarboxamides wherein a suitable primary amine is used in place ofammonia or ammonium hydroxide.

Likewise, carboxyester groups may be converted into carboxylic acidderivatives through basic or acidic hydrolysis conditions, widely knownin the art.

According to step (st.26) of the process, compounds of formula (I)wherein R₂ is hydroxy (—COOH) may be converted into carboxamidoderivatives (—CONR″R′″) or [—CON(OH)R″] wherein R″ and R′″ are asformerly indicated, also inclusive of compounds wherein R″ and R′″ form,together with the nitrogen atom to which they are bonded, a 5 or 6membered heteroaryl or heterocyclyl group optionally containing oneadditional heteroatom selected among N, O or S.

The reaction is carried out in the presence of an amine of formula(XXIII) or of a compound of formula (XXIV), as the case may be, underbasic conditions, preferably with N,N-diisopropyl-N-ethylamine ortriethylamine, in a suitable solvent such as dichloromethane,dimethylformamide, tetrahydrofuran, or dioxane, and in the presence of asuitable condensing agent such as N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethylisouronium tetrafluoroborate(TBTU); catalytic amounts of(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) ma be also required.

In addition, compounds of formula (I) wherein R—NH— is an amino (—NH₂)group may be easily converted into the corresponding carboxamido(—NHCOR) or ureido (—NHCONHR) derivatives, as set forth in steps (st.27)or (st.28) of the process, respectively. Typically, the reaction withisocyanate is performed with sodium hydride in dimethylformamide whilstthe one with the acid chloride may be carried out in a suitable solventsuch as pyridine, tetrahydrofuran, ethyl acetate or dioxane, or amixture of them at room temperature.

Compounds of formula (I) wherein R—NH— represents an arylamino orheteroarylamino group, can be obtained by the corresponding iododerivatives which, in their turn, may be prepared by the correspondingcompounds of formula (I) wherein R—NH— is amino, as per step (st.29) ofthe process.

The preparation of the iodo derivatives may be carried out in a suitablesolvent such as tetrahydrofuran, diethyl ether or dimethoxyethane, at atemperature ranging from room temperature to about 70° C., and for atime of about 8 hours to about 48 hours.

The subsequent conversion of the iododerivative may be carried out in asuitable solvent such as dimethylformamide, dimethoxyethane oracetonitrile and in the presence of catalytic amounts of palladiumacetate, (2,2′-bis(diphenylphosphino)-1,1′-binaphtalene (BINAP) and abase such as potassium carbonate, potassium phosphate or cesiumcarbonate, at a temperature ranging from room temperature to 110° C. andfor a time ranging from about 2 to about 24 hours.

Compounds of formula (I) wherein R is aryl and X is a single bond can beobtained, as reported in step (st.30), from the iodo derivative abovementioned by reaction with arylboronic acids of formula (XXVIII) in asuitable solvent such as dimethylformamide, dichloromethane, methanol,dimethoxyethane or acetonitrile, in the presence oftris(dibenzylideneacetone)dipalladium (0) or tetrakis triphenylphosphinopalladium [Pd(PPh₃)₄], optionally in the presence of cesium fluoride, ata temperature ranging from room temperature to 100° C.

Compounds of formula (I) wherein RNH— represents an alkylamino,cycloalkylamino, cycloalkyl-alkylamino, heterocyclylamino,heterocyclylalkylamino can be obtained from the corresponding iododerivative as set forth in step (st.29a) of the process. The reactionmay be carried out in a suitable solvent such as dimethylformamide,dioxane or acetonitrile or without solvent at a temperature ranging from40° C. to 120° C. for a time ranging from 3 to 18 hours.

Compounds of formula (I) wherein R—NH— is amino may be also convertedinto the corresponding alkylamino or arylmethylamino derivatives offormula (I) as reported in (st.31), by operating in a suitable solventor in a mixture of solvents, for instance comprising a 1:1:1 mixture ofacetic acid, methanol and water.

Compounds of formula (I) wherein R—NH— is amino may be also convertedinto the corresponding cycloalkylamino or heterocycloalkylaminoderivatives of formula (I) as reported in (st.31a), by operating in asuitable solvent such as methylene chloride, acetonitrile,dimethylformamide.

Compounds of formula (I) wherein R—X— represents an alkylthio group(R—S—) may be converted into a variety of compounds of formula (I)wherein X is —NH—, by first oxidizing the alkylthio to alkylsulfonylgroup and by replacing it with a R—NH— group, as reported in (st.32).The oxidative step may be carried out with oxone in the presence of asuitable solvent, preferably dimethylformamide or dimethylsulfoxide atroom temperature; the subsequent replacement of the alkylsulfonyl groupwith a suitable amino derivative is preferably carried out in thepresence of dimethylsulfoxide, dimethylformamide, dimethoxyethane,dioxane, acetonitrile, N-methyl-pyrrolidone or diglyme, at a temperatureranging from room temperature to about 100° C.

Interestingly, when the last step is carried out in the presence ofdimethylsulfoxide as a suitable solvent, this same solvent can also actas oxidizing agent capable of furnishing the desired compounds wherein Arepresents a group —CH═CH—. These latter derivatives are then separatedfrom the reaction mixture according to conventional methods, forinstance by chromatography or by preparative HPLC.

According to step (st.33) of the process, compounds of formula (I)wherein X is —O— may be easily obtained by reacting the sulfonylderivative with an alcohol or phenol derivative of formula (XXX) whereinR is as in formula (I). The reaction may be carried out in the presenceof a base such as potassium or sodium carbonate, butyl lithium, lithiumamide, sodium hydride or the like, in a suitable solvent such asdimethylformamide or tetrahydrofuran, and by working at a temperatureranging from room temperature to about 100° C.

Alternatively, according to steps (st.4d) and (st.33a), compounds offormula (I) wherein X is —O— may be obtained by reacting the compoundsof formula (Va) and (Vb) with methylisourea sulfate by operating in asuitable solvent such as dioxane, dimethylformamide or acetonitrile inthe presence of a base such as sodium or potassium carbonate at atemperature ranging from 50° C. to 100° C. The compounds of formula (I)wherein X is —O— and R is hydrogen may be obtained by reacting thecompounds of formula (I) wherein X is —O— and R is methyl withtrimethylsilyl chloride in the presence of sodium iodide and in asuitable solvent such as dioxane, tetrahydrofuran or acetonitrile atroom temperature. The compounds of formula (I) wherein X is —O— and R isa trifluorosulfonyl group may be obtained by reacting the compounds offormula (I) wherein X is —O— and R is hydrogen with a triflating agentsuch as trifluoromethanesulfonic anhydride,trifluoromethanesulfonylchloride orN-phenyl-bis(trifluoromethanesulfonimide), optionally in the presence ofa base such as triethylamine or N,N-diisopropyl-N-ethylamine (DIPEA), ina suitable solvent such as dichloromethane, tetrahydrofuran or dioxaneat a temperature ranging from −78° C. to room temperature.

The compounds of formula (I) wherein X is —O— and R is as describedabove may be obtained by reacting the compounds of formula (I) wherein Xis —O— and R is a trifluoromethanesulfonyl group with an alcohol orphenol of formula (XXX) wherein R is as in formula (I), by operating ina suitable solvent such as dioxane, tetrahydrofuran, dimethoxyethane,acetonitrile, dimethylformamide or dimethylsulfoxide, at a temperatureranging from room temperature to about 90° C., optionally in thepresence of a base such as potassium carbonate, potassium tertbutoxideor sodium hydride.

Alternatively the reaction may be carried out in a suitable solvent suchas toluene, dimethylformamide, dimethoxyethane or acetonitrile, in thepresence of palladium acetate, (±)-BINAP and a base such as potassiumphosphate (K₃PO₄) or potassium or cesium carbonate (K₂CO₃ or CsCO₃) at atemperature ranging from 0° C. to 100° C. (st.33c).

The compounds of formula (I) wherein X is —NH— and R is an optionallysubstituted alkyl, cycloalkyl, heterocyclyl, cycloalkyl-alkyl or aheterocyclylalkyl group may be obtained by reacting the compounds offormula (I) wherein X is —O— and R is a trifluoromethanesulfonyl groupwith an amine of formula R—NH₂ (XXVII) wherein R is as in formula (I),by operating in a suitable solvent such as dioxane, tetrahydrofuran,dimethoxyethane, acetonitrile, dimethylformamide or dimethylsulfoxide,at a temperature ranging from room temperature to 90° C., optionally inthe presence of a base such as potassium carbonate or triethylamine.

Finally, any of the above compounds of formula (I) wherein A representsa —CH₂—CH₂+ group can undergo dehydrogenation in the presence of anoptionally supported palladium or platinum catalyst, so as to give riseto the corresponding aromatic derivative wherein A is —CH═CH—, as per(st.34) of the process.

See the experimental section for any specific example concerning thepreparation of the compounds of formula (I) of the invention and theirconversion into other compounds of formula (I).

The intermediate compounds of formula (Va) or (Vb) according to step(st.3) of the process

and wherein R₁ is a hydrogen atom or an optionally substituted groupselected from straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl are novel and, hence,represent a further object of the invention.

According to any variant of the process for preparing the compounds offormula (I), the starting material and any other reactant is known oreasily prepared according to known methods.

As an example, 2-ethoxy-2-cyclohexen-1-one is a known compound which canbe easily obtained by refluxing cyclohexan-1,2-dione with ethanol intoluene, in the presence of catalytic amounts of p-toluenesulfonic acid(TsOH).

Likewise, 2-methoxy-4,4-dimethyl-2-cyclohexen-1-one is a known compoundwhich can be prepared through epoxidation of commercially available4,4-dimethyl-2-cyclohexen-1-one and subsequent treatment of the epoxidewith potassium hydroxide in methanol.

Finally, 2-methoxy-5,5-dimethyl-2-cyclohexen-1-one may be preparedaccording to the following scheme from commercially available5,5-dimethyl-cyclohexan-1,3-dione:

The compounds of formula (III), (VI), (VII), (XVI), (XXII), (XXIII),(XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX) and (XXX) are known oreasily prepared according to known methods.

Just as an example, when preparing given guanidino derivatives offormula (VI) wherein R is a rather complex chemical moiety, thefollowing scheme may be followed:

From all of the above, it is clear to the skilled man that whenpreparing the compounds of formula (I) according to any one of theaforementioned process variants, optional functional groups within thestarting materials or the intermediates thereof and which could giverise to unwanted side reactions, need to be properly protected accordingto conventional techniques. Likewise, the conversion of these latterinto the free deprotected compounds may be carried out according toknown procedures.

As it will be readily appreciated, if the compounds of formula (I)prepared according to the process described above are obtained as anadmixture of isomers, their separation into the single isomers offormula (I), according to conventional techniques, is within the scopeof the present invention.

Conventional techniques for racemate resolution include, for instance,partitioned crystallization of diastereoisomeric salt derivatives orpreparative chiral HPLC.

In addition, the compounds of formula (I) of the invention may be alsoprepared according to combinatorial chemistry techniques widely known inthe art, for instance by accomplishing the aforementioned reactionsbetween the several intermediates in a serial manner and by workingunder solid-phase-synthesis (SPS) conditions.

For a general reference to the preparation of the compounds of formula(I) of the invention according to combinatorial chemistry techniques,see the experimental section.

Hence, it is a further object of the present invention a library of twoor more compounds of formula (Ia) or (Ib)

wherein

R is hydrogen or an optionally substituted group selected from amino,straight or branched C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, cycloalkyl-alkyl,aryl, arylalkyl, heterocyclyl or heterocyclylalkyl;

X is a single bond or a divalent radical selected from —NR′—, —CONR′—,—NH—CO—NH—, —O—, —S— or —SO₂—, wherein R′ is hydrogen or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl or, together with the nitrogen atom to which they arebonded, R and R′ may form a 5 to 6 membered heteroaryl or heterocyclylgroup optionally containing one additional heteroatom selected among N,O or S;

R₁, bonded to any one of the nitrogen atoms of the pyrazole ring as performulae (Ia) or (Ib), represents a hydrogen atom or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, informula (Ib), R₁ is a divalent —(CH₂)_(n)—NH— group being linked toR_(z) wherein n is 2 or 3;

R₂ is a group selected from —NR″R′″, —N(OH)R″, —OR″ or —R″, wherein R″and R′″ are, each independently, hydrogen or an optionally substitutedgroup selected from straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkylor cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkylor, together with the nitrogen atom to which they are bonded, R″ and R′″may form a 5 to 6 membered heteroaryl or heterocyclyl group, optionallycontaining one additional heteroatom selected among N, O or S;

A is a divalent group selected from —CH₂—, —(CH₂)₂—, —CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂— or —CH═CH—;

or a pharmaceutically acceptable salt thereof.

Pharmacology

The compounds of formula (I) are active as protein kinase inhibitors andare therefore useful, for instance, to restrict the unregulatedproliferation of tumor cells.

In therapy, they may be used in the treatment of various tumors, such asthose formerly reported, as well as in the treatment of other cellproliferative disorders such as psoriasis, vascular smooth cellproliferation associated with atherosclerosis and post-surgical stenosisand restenosis and in the treatment of Alzheimer's disease.

The inhibiting activity of putative cdk/cyclin inhibitors and thepotency of selected compounds is determined through a method of assaybased on the use of the SPA technology (Amersham Pharmacia Biotech).

The assay consists of the transfer of radioactivity labelled phosphatemoiety by the kinase to a biotinylated substrate. The resulting33P-labelled biotinylated product is allowed to bind tostreptavidin-coated SPA beads (biotin capacity 130 pmol/mg), and lightemitted was measured in a scintillation counter.

Inhibition Assay of Cdk2/Cyclin A Activity

Kinase reaction: 4 μM in house biotinylated histone H1 (Sigma # H-5505)substrate, 10 μM ATP (0.1 microCi P³³γ-ATP), 1.1 nM Cyclin A/CDK2complex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a96 U bottom. After incubation for 60 min at room temperature, thereaction was stopped by addition of 100 μl PBS buffer containing 32 mMEDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coatedSPA beads. After 20 min incubation, 110 μL of suspension were withdrawnand transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl.After 4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC₅₀ determination: inhibitors were tested at different concentrationsranging from 0.0015 to 10 μM. Experimental data were analyzed by thecomputer program GraphPad Prizm using the four parameter logisticequation:y=bottom+(top−bottom)/(1+10^((log IC50−x)*slope))where x is the logarithm of the inhibitor concentration, y is theresponse; y starts at bottom and goes to top with a sigmoid shape.Ki Calculation:

Experimental Method:

Reaction was carried out in buffer (10 mM Tris, pH 7.5, 10 mM MgCl₂, 0.2mg/ml BSA, 7.5 mM DTT) containing 3.7 nM enzyme, histone and ATP(constant ratio of cold/labeled ATP 1/3000). Reaction was stopped withEDTA and the substrate captured on phosphomembrane (Multiscreen 96 wellplates from Millipore). After extensive washing, the multiscreen plateswere read on a top counter. Control (time zero) for each ATP and histoneconcentrations was measured.

Experimental Design:

Reaction velocities are measured at four ATP, substrate (histone) andinhibitor concentrations. An 80-point concentration matrix was designedaround the respective ATP and substrate Km values, and the inhibitorIC50 values (0.3, 1, 3, 9 fold the Km or IC50 values). A preliminarytime course experiment in the absence of inhibitor and at the differentATP and substrate concentrations allows the selection of a singleendpoint time (10 min) in the linear range of the reaction for the Kidetermination experiment.

Kinetic Parameter Estimates:

Kinetic parameters were estimated by simultaneous nonlinear least-squareregression using [Eq.1] (competitive inhibitor respect to ATP, randommechanism) using the complete data set (80 points):

$\begin{matrix}{v = \frac{{Vm} \cdot A \cdot B}{\begin{matrix}{{\alpha \cdot {Ka} \cdot {Kb}} + {\alpha \cdot {Ka} \cdot B} +} \\{{a \cdot {Kb} \cdot A} + {A \cdot B} + {\alpha \cdot \frac{Ka}{Ki} \cdot I \cdot ( {{Kb} + \frac{B}{\beta}} )}}\end{matrix}}} & \lbrack {{Eq}.\mspace{14mu} 1} \rbrack\end{matrix}$where A=[ATP], B=[Substrate], I=[inhibitor], Vm=maximum velocity, Ka,Kb, Ki the dissociation constants of ATP, substrate and inhibitorrespectively. α and β the cooperativity factor between substrate and ATPbinding and substrate and inhibitor binding respectively.

In addition the selected compounds are characterized on a panel ofser/thre kinases strictly related to cell cycle (cdk2/cyclin E,cdk1/cyclin B1, cdk5/p25, cdk4/cyclin D1), and also for specificity onMAPK, PKA, EGFR, IGF1-R, Aurora-2 and Cdc 7

Inhibition Assay of Cdk2/Cyclin E Activity

Kinase Reaction:

10 μM □ in house biotinylated histone H1 (Sigma # H-5505) substrate, 30μM □ATP (0.3 microCi P³³γ-ATP), 4 ng GST-Cyclin E/CDK2 complex,inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After incubation for 60 min at room temperature, the reactionwas stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPAbeads. After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC₅₀ determination: see above

Inhibition Assay of Cdk1/Cyclin B1 Activity

Kinase Reaction:

4 μM in house biotinylated histone H1 (Sigma # H-5505) substrate, 20 μMATP (0.2 microCi P³³γ-ATP), 3 ng Cyclin B/CDK1 complex, inhibitor in afinal volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM, DTT7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After 20min at r.t. incubation, reaction was stopped by 100 μl PBS+32 mMEDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPA beads. Then avolume of 110 μl is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the Optiplate andlet stand 4 hours before radioactivity counting in the Top-Countinstrument.

IC₅₀ determination: see above

Inhibition Assay of Cdk5/p25 Activity

The inhibition assay of cdk5/p25 activity is performed according to thefollowing protocol.

Kinase Reaction:

10 μM biotinylated histone H1 (Sigma # H-5505) substrate, 30 μM ATP (0.3microCi P³³γ-ATP), 15 ng CDK5/p25 complex, inhibitor in a final volumeof 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2mg/ml BSA) were added to each well of a 96 U bottom. After incubationfor 35 min at room temperature, the reaction was stopped by addition of100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% TritonX100 and 10 mg/ml streptavidin coated SPA beads. After 20 minincubation, 110 μL of suspension were withdrawn and transferred into96-well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, theplates were read for 2 min in a Packard TOP-Count radioactivity reader.

IC₅₀ determination: see above

Inhibition Assay of Cdk4/Cyclin D1 Activity

Kinase Reaction:

0.4 μM mouse GST-Rb (769-921) (# sc-4112 from Santa Cruz) substrate, 10μM ATP (0.5 μCi P³³γ-ATP), 100 ng of baculovirus expressedGST-cdk4/GST-Cyclin D1, suitable concentrations of inhibitor in a finalvolume of 50 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM, 7.5 mMDTT+0.2 mg/ml BSA) were added to each well of a 96 U bottom well plate.After 40 min at 37° C. incubation, reaction was stopped by 20 μl EDTA120 mM.

Capture:

60 μl were transferred from each well to MultiScreen plate, to allowsubstrate binding to phosphocellulose filter. Plates were then washed 3times with 150 μl/well PBS Ca⁺⁺/Mg⁺⁺ free and filtered by MultiScreenfiltration system.

Detection: filters were allowed to dry at 37° C., then 100 μl/wellscintillant were added and ³³P labeled Rb fragment was detected byradioactivity counting in the Top-Count instrument.

IC₅₀ determination: see above

Inhibition Assay of MAPK Activity

Kinase Reaction:

10 μM in house biotinylated MBP (Sigma # M-1891) substrate, 15 μM ATP(0.15 microCi P³³γ-ATP), 30 ng GST-MAPK (Upstate Biothecnology #14-173),inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After incubation for 35 min at room temperature, the reactionwas stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPAbeads. After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC₅₀ determination: see above

Inhibition Assay of PKA Activity

Kinase Reaction:

10 μM in house biotinylated histone H1 (Sigma # H-5505) substrate, 10 μMATP (0.2 microM P³³γ-ATP), 0.45 U PKA (Sigma #2645), inhibitor in afinal volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM, DTT7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. Afterincubation for 90 min at room temperature, the reaction was stopped byaddition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP,0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20min incubation, 110 μL of suspension were withdrawn and transferred into96-well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, theplates were read for 2 min in a Packard TOP-Count radioactivity reader.

IC₅₀ determination: see above

Inhibition Assay of EGFR Activity

Kinase Reaction:

10 μM in house biotinylated MBP (Sigma # M-1891) substrate, 2 μM ATP(0.04 microCi P³³γ-ATP), 36 ng insect cell expressed GST-EGFR, inhibitorin a final volume of 30 μl buffer (Hepes 50 mM pH 7.5, MgCl₂ 3 mM, MnCl₂3 mM, DTT 1 mM, NaVO₃ 3 μM, +0.2 mg/ml BSA) were added to each well of a96 U bottom. After incubation for 20 min at room temperature, thereaction was stopped by addition of 100 μl PBS buffer containing 32 mMEDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coatedSPA beads. After 20 min incubation, 110 μL of suspension were withdrawnand transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl.After 4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC₅₀ determination: see above

Inhibition Assay of IGF1-R Activity

The inhibition assay of IGF1-R activity is performed according to thefollowing protocol.

Enzyme Activation:

IGF1-R must be activated by auto-phosphorylation before starting theexperiment. Just prior to the assay, a concentrated enzyme solution (694nM) is incubated for half a hour at 28° C. in the presence of 100 μM ATPand then brought to the working dilution in the indicated buffer.

Kinase Reaction:

10 μM biotinylated IRS 1 peptide (PRIMM) substrate, 0-20 μM inhibitor, 6μM ATP, 1 microCi ³³P-ATP, and 6 nM GST-IGF1-R (pre-incubated for 30 minat room temperature with cold 60 μM cold ATP) in a final volume of 30 μlbuffer (50 mM HEPES pH 7.9, 3 mM MnCl₂, 1 mM DTT, 3 μM NaVO₃) were addedto each well of a 96 U bottom well plate. After incubation for 35 min atroom temperature, the reaction was stopped by addition of 100 μl PBSbuffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL ofsuspension were withdrawn and transferred into 96-well OPTIPLATEscontaining 100 μl of 5M CsCl. After 4 hours, the plates were read for 2min in a Packard TOP-Count radioactivity reader.

Inhibition Assay of Aurora-2 Activity

Kinase Reaction:

8 μM biotinylated peptide (4 repeats of LRRWSLG), 10 μM ATP (0.5 uCiP³³γ-ATP), 7.5 ng Aurora 2, inhibitor in a final volume of 30 μl buffer(HEPES 50 mM pH 7.0, MgCl₂ 10 mM, 1 mM DTT, 0.2 mg/ml BSA, 3 μMorthovanadate) were added to each well of a 96 U bottom well plate.After 60 minutes at room temperature incubation, reaction was stoppedand biotinylated peptide captured by adding 100 μl of bead suspension.

Stratification:

100 μl of CsCl2 5 M were added to each well and let stand 4 hour beforeradioactivity was counted in the Top-Count instrument.

IC₅₀ determination: see above

Inhibition Assay of Cdc7/Dbf4 Activity

The inhibition assay of Cdc7/dbf4 activity is performed according to thefollowing protocol.

The Biotin-MCM2 substrate is trans-phosphorylated by the Cdc7/Dbf4complex in the presence of ATP traced with γ³³-ATP. The phosphorylatedBiotin-MCM2 substrate is then captured by Streptavidin-coated SPA beadsand the extent of phosphorylation evaluated by β counting.

The inhibition assay of Cdc7/dbf4 activity was performed in 96 wellsplate according to the following protocol.

To each well of the plate were added:

-   -   10 μl substrate (biotinylated MCM2, 6 μM final concentration)    -   10 μl enzyme (Cdc7/Dbf4, 17.9 nM final concentration)    -   10 μl test compound (12 increasing concentrations in the nM to        μM range to generate a dose-response curve)    -   10 μl of a mixture of cold ATP (2 μM final concentration) and        radioactive ATP (1/5000 molar ratio with cold ATP) was then used        to start the reaction which was allowed to take place at 37° C.

Substrate, enzyme and ATP were diluted in 50 mM HEPES pH 7.9 containing15 mM MgCl₂, 2 mM DTT, 3 μM NaVO₃, 2 mM glycerophosphate and 0.2 mg/mlBSA. The solvent for test compounds also contained 10% DMSO.

After incubation for 60 minutes, the reaction was stopped by adding toeach well 100 μl of PBS pH 7.4 containing 50 mM EDTA, 1 mM cold ATP,0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads.

After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

IC₅₀ determination: see above.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with cytostatic or cytotoxic agents, antibiotic-type agents,alkylating agents, antimetabolite agents, hormonal agents, immunologicalagents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors,tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HERagents, anti-EGFR agents, anti-angiogenesis agents (e.g. angiogenesisinhibitors), farnesyl transferase inhibitors, ras-raf signaltransduction pathway inhibitors, cell cycle inhibitors, other cdksinhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) may be used sequentially with known anticanceragents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight,conditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of acompound of formula (I) may range from about 10 to about 500 mg perdose, from 1 to 5 times daily. The compounds of the invention can beadministered in a variety of dosage forms, e.g., orally, in the formtablets, capsules, sugar or film coated tablets, liquid solutions orsuspensions; rectally in the form suppositories; parenterally, e.g.,intramuscularly, or through intravenous and/or intrathecal and/orintraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose saccharose, sucrose,cellulose, corn starch or potato starch; lubricants, e.g., silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g., starches, arabic gum, gelatinemethylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disintegrating agents, e.g., starch, alginic acid, alginates or sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents such as lecithin, polysorbates, laurylsulphates; and, in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. These pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions.

As an example, the syrups may contain, as carrier, saccharose orsaccharose with glycerine and/or mannitol and sorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g.,propylene glycol and, if desired, a suitable amount of lidocainehydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

With the aim to better illustrate the present invention, without posingany limitation to it, the following examples are now given.

EXAMPLES

Several compounds of formula (I), hence including those of formula (Ia)and (Ib) of the invention, have been prepared. Whilst some of them havebeen specifically named and listed in the following experimentalsection, most have been conveniently identified as per the coding systemof the tables reported in the experimental section, together with theiranalytical data.

Each code, which unambiguosly identifies a single specific compound offormula (I) only, consists of five units B—X-M(C)-D.

Code B represents any R substituent, as per formula (I), being attachedto the rest of the molecule through the X linkage; each B group isrepresented through the proper chemical formula in the following tableI, also indicating its point of attachment to the rest of the moleculeX-M.

Code X just represents the X group in formula (I); its meanings arerepresented in the following table II, also indicating its point ofattachment to the rest of the molecule M.

Code C represents the R₁ group being attached to the rest of themolecule through any one of the pyrazole nitrogen atoms, as per formula(I). Each C group is represented through the proper chemical formula inthe following table III, also indicating its point of attachment to therest of the molecule M.

Code D represents the R₂ group being attached to the rest of themolecule through the carbonyl group, as per formula (I). Each D group isrepresented through the proper chemical formula in the following tableIV, also indicating its point of attachment to the rest of the moleculeM.

Finally, code M refers to the central core of the molecule (I) bearing acarbonyl group in position 3. From all of the above it is clear to theskilled person that M is substituted by groups —X— (code X), R₁ (code C)and R₂ (code D), as reported in formula (I); each M group is representedthrough the proper chemical formula, in table V, also indicating thepositions of the other substituents.

Therefore, the coding system presently used for some compounds offormula (I) can be shortly summarised as follows:

Just as an example, which is not intended to limit the scope of thepresent invention, the compound B66-X03-M00(C01)-D01 (see example 36)represents the pyrazolo-quinazoline derivative of formula (Ia) whereinthe central core is represented by the moiety MOO of table V, R is thegroup of formula B66 of table I, X is the divalent group X03 of tableII, R₁ is the group C01 of table III and R₂ is the group D01 of tableIV, having formula

From all of the above, it is clear to the skilled person that when R₁and R₂ are linked together as per formula (Ib), then this additionalcycle is already included in the structure of the M moiety and, hence,codes C and D are missing.

TABLE I TABLE OF B GROUPS Fragment Code

B00

B01

B02

B03

B04

B05

B06

B07

B08

B09

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

B31

B32

B33

B34

B35

B36

B37

B38

B39

B40

B41

B42

B43

B44

B45

B46

B47

B48

B49

B50

B51

B52

B53

B54

B55

B56

B57

B58

B59

B60

B61

B62

B63

B64

B65

B66

B67

B68

B69

B70

B71

B72

B73

B74

B75

B76

B77

B78

B79

B80

B81

B82

B83

B84

B85

B86

B87

B88

B89

B90

B91

B92

B93

B94

B95

B96

B97

B98

B99

B100

B101

B102

B103

B104

B105

B106

B107

B108

B109

B110

B111

B112

B113

B114

B115

B116

B117

B118

B119

B120

B121

B122

B123

B124

B125

B126

B127

B128

B129

B130

B131

B132

B133

B134

B135

B136

B137

B138

B139

B140

B141

B142

B143

B144

B145

B146

B147

B148

B149

B150

B151

B152

B153

B154

B155

B156

B157

B158

B159

B160

B161

B162

B163

B164

B165

B166

B167

B168

B169

B170

B171

B172

B173

TABLE II TABLE OF X LINKERS Fragment Code —NH-M X00 —CONH-M X01—NHCONH-M X02 —O-M X03 —S-M X04 —SO₂-M X05 —M X06

TABLE III TABLE OF C GROUPS Fragment Code   M—H C00 M—Me C01 M—tBu C02

C03

C04

C05

C06

C07

C08

C09

C10

C11

C12

C13

C14

C15

C16

C17

C18

C19

C20

C21

C22

C23

C24

TABLE IV TABLE OF D GROUPS Fragment Code   M—OMe D00  M—OEt D01  M—OHD02  M—NH₂ D03 

D04  M—NH—OH D05 

D06  M—Ph D07 

D08 

D09 

D10 

D11 

D12 

D13 

D14 

D15 

D16 

D17 

D18 

D19 

D20 

D21 

D22 

D23 

D24 

D25 

D26 

D27 

D28 

D29 

D30 

D31 

D32 

D33 

D34 

D35 

D36 

D37 

D38 

D39 

D40 

D41 

D42 

D43 

D44 

D45 

D46 

D47 

D48 

D49 

D50 

D51 

D52 

D53 

D54 

D55 

D56 

D57 

D58 

D59 

D60 

D61 

D62 

D63 

D64 

D65 

D66 

D67 

D68 

D69 

D70 

D71 

D72 

D73 

D74 

D75 

D76 

D77 

D78 

D79 

D80 

D81 

D82 

D83 

D84 

D85 

D86 

D87 

D88 

D89 

D90 

D91 

D92 

D93 

D94 

D95 

D96 

D97 

D98 

D99 

D100

D101

D102

D103

D104

D105

D106

D107

D108

D109

D110

D111

D112

D113

D114

D115

D116

D117

D118

D119

D120

D121

D122

D123

D124

D125

D126

D127

D128

D129

D130

D131

D132

D133

D134

D135

D136

D137

D138

D139

D140

D141

D142

D143

D144

D145

D146

D147

D148

D149

D150

D151

D152

D153

D154

D155

D156

D157

D158

D159

D160

D161

D162

D163

D164

D165

TABLE V TABLE OF M CORE Structure Code  

M00

M01

M02

M03

M04

M05

M06

M07

M08

M09

M10

M11

The compounds of the present invention, as prepared according to thefollowing examples, were also characterized by ¹H NMR and/or by HPLC/MSanalytical data; HPLC/MS data were collected following any one ofmethods 1, 2 or 3.

HPLC/MS Method 1

The HPLC equipment consisted of a Waters 2790 HPLC system equipped witha 996 Waters PDA detector and Micromass mod. ZQ single quadrupole massspectrometer, equipped with an electrospray (ESI) ion source. Instrumentcontrol, data acquisition and data processing were providen by Empowerand MassLynx 4.0 software.

HPLC was carried out at 25° C. at a flow rate of 1 mL/min using a RP18Waters X Terra (4.6×50 mm, 3.5 pin) column. Mobile phase A was ammoniumacetate 5 mM buffer (pH 5.5 with acetic acid/acetonitrile 95:5), andMobile phase B was H₂O/acetonitrile (5:95); the gradient was from 10 to90% B in 8 minutes then hold 90% B 2 minutes. The injection volume was10 μl.

The mass spectrometer was operated in positive and in negative ion mode,the capillary voltage was set up at 2.5 KV; the source temperature was120° C.; cone was 10 V; full scan, mass range from 100 to 800 amu wasset up.

HPLC/MS Method 2

The HPLC equipment consisted of a Waters 2790 HPLC system equipped witha 996 Waters PDA detector and Micromass mod. ZQ single quadrupole massspectrometer, equipped with an electrospray (ESI) ion source. Instrumentcontrol, data acquisition and data processing were providen by Empowerand MassLynx 4.0 software.

HPLC was carried out at 25° C. at a flow rate of 1 mL/min using a RP18Waters X Terra (3.0×30 mm, 3.5 μm) column. Mobile phase A was ammoniumacetate 5 mM buffer (pH 5.5 with acetic acid/acetonitrile 95:5), andMobile phase B was H₂O/acetonitrile (5:95); the gradient was from 10 to90% B in 4 min then hold 90% B 1 minute. The injection volume was 10 μl.

The mass spectometer was operated in positive and in negative ion mode,the capillary voltage was set up at 2.5 KV; the source temperature was120° C.; cone was 10 V; full scan, mass range from 100 to 800 amu wasset up.

HPLC/MS Method 3

Mass spectra were recorded on a Finnigan LCQ ion trap mass spectrometerusing the electrospray (ESI) ionization technique with positive andnegative ion detection. The mass spectrometer is directly connected to aSSP4000 HPLC system (Thermo Separation), equipped with an LcPalautosampler (CTC Analytics) and a UV 6000LP PDA detector (ThermoSeparation). Instrument control, data acquisition and processing wereperformed by using Xcalibur 1.2 software. HPLC analysis were carried outat room temperature at a flow rate of 1 mL/min using an RP C18 WatersZorbaxSB C18 column (4.6×50 mm; 1.8 μm).

Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with aceticacid): acetonitrile 90:10, and Mobile phase B was ammonium acetate 5 mMbuffer (pH 5.5 with acetic acid): acetonitrile 10:90; the gradient wasfrom 0 to 100% B in 7 minutes then hold 100% B for 2 minutes beforerequilibration. Total LC time is 12 minutes. The injection volume was104 UV Detection was performed between 215 and 400 nm

Ions were generated under the following conditions: ESI sprayer voltage4.0 kV, heated capillary temperature 255° C., sheath gas nitrogen with apressure of 5.0 Bar. A full scan detection mode (from 50 to 1000 amu)was used with an MS/MS analysis of the most intense ion (normalizedcollision energy: 35%).

UV Detection: 215-400 nm.

Example 1 2-ethoxycyclohex-2-en-1-one

50 g (0.45 mol) of 1,2-dicyclohexandione were dissolved in a mixture of1 L of toluene and 0.5 L of ethanol. 10 g of p-toluenesulfonic acid wereadded and the solution heated at reflux for 2 days. (TLCchloroform/methanol 6/1). The solvent was then evaporated, the residueredissolved with dichloromethane and washed with a saturated solution ofNaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. Thecrude was purified by chromatography on a silica gel column by elutingwith a mixture of cyclohexane/ethyl acetate 98/2 (66% yield as an oil).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, 3H) 2.33-2.39 (m, 6H) 3.67 (q,2H) 5.97 (t, 1H).

Example 2 Ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate

41.40 g (0.29 mol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 310mL of diethyl ether and 325 mL of 1M LiN(TMS)₂ in tetrahydrofuran wereadded dropwise at −50° C. After 30 minutes at the same temperature, 44.2mL of diethyloxalate were also added under stirring. The solution waskept at room temperature overnight (TLC chloroform). 300 mL of waterwere then added, the pH adjusted to 4-5 by adding 1 N HCl and theresulting solution extracted with ethyl acetate. The organic layer wasdried over Na₂SO₄ and evaporated to dryness. The crude was purified bychromatography on a silica gel column eluted by chloroform (76% yield asan oil).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (t, 3H) 1.51 (t, 3H) 2.06-2.58 (m,4H) 3.57 (m, 1H) 3.86 (q, 2H) 4.38 (q, 2H) 6.09 (m, 1H).

Example 3 Ethyl1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

30 g (0.125 mol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetatewere dissolved in 150 mL of glacial acetic acid and 6.5 mL ofmethylhydrazine were added. The mixture was stirred at room temperaturefor 6 hours. The solvent was then evaporated and the crude redissolvedwith water, the solution made basic with 30% NH₄OH and extracted withchloroform. The organic layer was then dried over Na₂SO₄ andconcentrated. The residue was chromatographed on a silica gel column(eluant: chloroform) and crystallized from a mixture n-hexane/diethylether (TLC chloroform; 63% yield as a white solid).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (t, J 6.89 Hz, 3H) 1.51 (t, J 6.94Hz, 3H) 2.06-2.58 (m, 4H) 3.57 (m, 1H) 3.86 (q, J 6.83 Hz, 2H) 4.38 (q,J 6.94 Hz, 2H; 6.09 (m, 1H).

According to the same method, but employing the suitable substitutedhydrazine derivative, the following compounds were prepared:

-   ethyl    1-tert-butyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (t, J 6.83 Hz, 3H) 1.58 (s, 9H)2.30-2.93 (3m, 6H) 4.18 (q, J 6.83 Hz, 2H);

-   ethyl    1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz), DMSO-d₆) δ ppm 1.3 (t, J 7.20 Hz, 3H) 1.9-2.9 (3m, 6H)3.7 (m, 2H) 4.3 (q, J 7.20 Hz, 2H) 4.53 (t, J 5.85, 2H) 4.77 (t, J 5.73,OH);

-   ethyl    1-(2-ethoxy-2-oxoethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz), DMSO-d₆) δ ppm 1.18 (t, J 7.20 Hz, 3H) 1.29 (t, J 7.20Hz, 3H) 2.04 (m, 2H); 2.52 (m, 2H) 2.93 (t, J 6.10 Hz, 2H) 4.04 (q, J7.07 Hz, 2H) 4.37 (q, J 7.20 Hz, 2H) 5.26 (s, 1H);

-   ethyl    7-oxo-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J 7.07 Hz, 3H) 2.05 (m, 2H)2.57 (m, 2H) 2.95 (m, 2H) 4.2 (q, J 7.07 Hz, 2H) 5.3 (2d, 2H);

-   ethyl    7-oxo-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t, J 7.08 Hz, 3H) 2.05 (m, 2H)2.57 (t, J 7.44 Hz, 2H) 2.94 (m, 2H) 4.30 (q, J 7.19 Hz, 2H) 5.46 (2d,2H);

-   ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (t, J=7.07 Hz, 3H) 2.04 (m, 2H)2.51 (m, 2H) 2.87 (t, J=6.10 Hz, 2H) 4.27 (q, J=7.11 Hz, 2H) 14.39 (s,1H);

-   ethyl    1-[4-(aminosulfonyl)phenyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, J=7.13 Hz, 3H) 2.10-2.19 (m,2H) 2.57-2.63 (m, 2H) 3.05 (t, J=6.10 Hz, 2H) 4.37 (q, J=7.07 Hz, 2H)7.54 (s, 2H) 7.77 (d, J=8.78 Hz, 2H) 7.96 (d, J=8.90 Hz, 2H);

-   ethyl    1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.07 Hz, 3H) 2.05-2.17 (m,2H) 2.56 (dd, J=7.26, 5.55 Hz, 2H) 3.03 (t, J=6.10 Hz, 2H) 3.85 (s, 3H)4.34 (q, J=7.07 Hz, 2H) 7.05 (d, J=9.02 Hz, 2H) 7.44 (d, J=9.02 Hz, 2H);

-   ethyl    1-(4-cyanophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, J=7.07 Hz, 3H) 2.09-2.19 (m,2H) 2.60 (dd, J=7.32, 5.49 Hz, 2H) 3.04 (t, J=6.16 Hz, 2H) 4.36 (q,J=7.11 Hz, 2H) 7.80 (d, J=8.90 Hz, 2H) 8.03 (d, J=8.78 Hz, 2H);

-   ethyl    7-oxo-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, J=7.13 Hz, 3H) 2.10-2.21 (m,2H) 2.58 (dd, J=7.32, 5.61 Hz, 2H) 3.05 (t, J=6.16 Hz, 2H) 4.36 (q,J=7.07 Hz, 2H) 7.61 (ddd, J=7.41, 4.73, 1.04 Hz, 1H) 7.64 (dt, J=7.93,0.98 Hz, 1H) 8.07 (td, J=7.74, 1.83 Hz, 1H) 8.57 (ddd, J=4.79, 1.86,0.79 Hz, 1H);

-   ethyl 7-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (t, 3H, J 7.08) 2.08 (m, 2H) 2.54(m, 2H) 4.30 (q, 2H, J 7.08) 7.49 (m, 5H);

-   ethyl 1-benzyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    1-(1-methylpiperidin-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.84-2.11 (m,6H) 2.28 (s, 3H) 2.48-2.53 (m, 2H) 2.52-2.60 (m, 2H) 2.91-3.00 (m, 2H)2.94 (t, J=6.16 Hz, 2H) 4.32 (q, J=7.15 Hz, 2H) 4.93-5.11 (m, 1H)

(The hydrazino derivative being employed was not commercially available(CAS no 53242-78-7) and was thus synthetized as described in theliterature: WO 02/085906).

-   ethyl    7-oxo-1-piperidin-4-yl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

(The hydrazino derivative being employed was not commercially availableand was thus synthetized as described in the literature: DE 3634942 A1).

-   ethyl    1-(1-benzylpiperidin-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, 3H, J 7.07 Hz) 3.34 (s, 2H)4.31 (q, 2H, J 7.07 Hz) 5.06 (m, 1H) 7.35 (m, 5H);

-   ethyl    1-(1-acetylpiperidin-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

(The hydrazino derivative being employed was not commercially availableand was thus synthetized as reported in example 69).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (bs, 3H) 2.59 (m, 1H) 2.71 (m, 1H)2.95 (m, 1H) 3.29 (m, 1H) 3.94 (m, 1H) 4.30 (m, 2H) 4.48 (m, 1H) 5.29(m, 1H)

-   ethyl    1-(2-dimethylaminoethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    1-(2-dimethylaminopropyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Example 4 Ethyl1(2)-(3,3-dimethylbutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Step 1. Ethyl 7-ethoxy-4,5-dihydro-1H-indazole-3-carboxylate

1.2 g (5 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetatewere dissolved in 20 mL of ethanol and 25 mL (5.2 mmol) of hydrazinehydrate 98% were added dropwise. The solution was stirred at roomtemperature for 5 hours, then heated at 60° C. for further 5 hours. Thesolvent was removed in vacuo and the residue taken up with diethyl etherand the resulting precipitate collected by filtration giving 0.8 g ofthe title compound, that was employed in the next step without anyfurther purification.

Step 2. Ethyl1(2)-(3,3-dimethylbutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

0.28 g (1.17 mmol) of ethyl7-ethoxy-4,5-dihydro-1H-indazole-3-carboxylate were dissolved in 12 mLof dry dimethylformamide and 0.25 g (1.40 mmol) of 3,3-dimethylbutylmethanesulfonate were added. The resulting solution was treated with0.06 g (1.40 mmol) of sodium hydride 60% in mineral oil and the reactionmixture stirred at 65° C. for 4 hours. Water was added to the reactionand the solution extracted with ethyl acetate. The solvent wasevaporated in vacuo and the residue redissolved with 10 mL of methanol.Few drops of 1 N HCl were then added and after 3 hours the reaction waspartitioned between water and ethyl acetate, giving a crude that, afterdrying over Na₂SO₄, was purified by chromatography on a silica gelcolumn (eluant hexane/ethyl acetate 95/5) (75% yield).

Example 5 Ethyl7-oxo-1(2)-[(5-phenyl-1,3-oxazol-2-yl)methyl]-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

900 mg (4.3 mmol) of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 26mL of DMF and 712 mg (5.16 mmol) of K₂CO₃ and 995 mg (5.16 mmol) of2-(chloromethyl)-5-phenyl-1,3-oxazole were added. The reaction mixturewas stirred at room temperature for 5 hours then the solvent was removedunder vacuo and the residue was dissolved in dichloromethane and washedwith water. The organic layer was dried over Na₂SO₄ and evaporated todryness. By chromatography, 405 mg (30% yield) of the two regioisomerswere recovered.

-   ethyl    7-oxo-1-[(5-phenyl-1,3-oxazol-2-yl)methyl]-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t, 3H) 2.09 (m, 2H) 2.59 (m, 2H)2.97 (m, 2H) 4.31 (q, 2H) 6.04 (s, 2H) 7.39 (m, 1H) 7.49 (m, 2H) 7.63(s, 1H) 7.66 (m, 2H)

-   ethyl    7-oxo-2-[(5-phenyl-1,3-oxazol-2-yl)methyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, 3H) 2.09 (m, 2H) 2.60 (m, 2H)2.99 (m, 2H) 4.31 (q, 2H) 5.98 (s, 2H) 7.39 (m, 1H) 7.49 (m, 2H) 7.62(s, 1H) 7.66 (m, 2H).

Example 6 Ethyl1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Step 1.[3-(ethoxycarbonyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazol-1(2)-yl]aceticacid

1 g (4.8 mmol) of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 30mL of dry DMF and treated with 1.59 g (11.52 mmol) of K₂CO₃ and 800 mg(5.76 mmol) of bromoacetic acid at room temperature. After heating at80° C. overnight the mixture was cooled and the solvent was removedunder vacuo. The crude was dissolved in water and neutralized with HCl37%. Three extractions with dichloromethane afforded 1.7 g of crude thatwas purified by flash chromatography (eluant dichloromethane) yielding783 mg (61%) of the product as mixture of regioisomers.

Step 2. Ethyl7-oxo-1(2)-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

743 mg (2.79 mmol) of[3-(ethoxycarbonyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazol-1(2)-yl]aceticacid as mixture of isomers were dissolved in 28 mL of DMF and 2.18 g(4.18 mmol) of benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 690 mg (5.58 mmol) of 1-aminobutan-2-onehydrochloride and 2.4 mL (13.95 mmol) of N-ethyl-N,N-diisopropylaminewere added. After 2 hours the solvent was evaporated under vacuo, thecrude was dissolved in dichloromethane and washed with saturated NaHCO₃,brine and water. Purification by flash chromatography (eluanthexane/ethylacetate 8/2) yielded 511 mg of ethyl7-oxo-1-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylateand 20 mg of ethyl7-oxo-2-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate(57% overall yield).

-   ethyl    7-oxo-1-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (t, 3H) 1.32 (t, 3H) 2.09 (m, 2H)2.44 (q, 2H) 2.52 (t, 2H) 2.96 (t, 2H) 3.98 (d, 2H) 4.31 (q, 2H) 5.26(s, 2H) 8.44 (t, 1H);

-   ethyl    7-oxo-2-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (t, 3H) 1.31 (t, 3H) 2.08 (m, 2H)2.44 (q, 2H) 2.53 (t, 2H) 2.94 (t, 2H) 3.99 (d, 2H) 4.29 (q, 2H) 5.32(s, 2H) 8.48 (t, 1H).

Step 3. Ethyl1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

A solution of 506 mg (1.51 mmol) of ethyl7-oxo-1-{2-oxo-2-[(2-oxobutyl)amino]ethyl}-4,5,6,7-tetrahydro-1H-indazole-3-carboxylatein toluene (45 mL) was treated with 0.422 mL (4.53 mmol) of phosphorictrichloride and heated at 90° C. for 15 hours. The mixture was cooled toroom temperature, poured into ice and neutralized with NaOH 5N. Theaqueous phase was extracted with dichloromethane and the organic layerafforded 425 mg of crude that was purified on silica gel (eluanthexane/ethylacetate 7/3). 285 mg of the title compound were thusisolated (60% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (t, 3H) 1.32 (t, 3H) 2.08 (m, 2H)2.63 (m, 4H) 2.97 (t, 2H) 4.31 (q, 2H) 5.84 (s, 2H) 6.79 (s, 1H).

Example 7 Ethyl6-[(dimethylamino)methylene]-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

16 g (0.07 mol) of ethyl1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate weredissolved in 100 mL of dimethylformamide and 32 mL of dimethylformamideditertbutyl acetate were added. The mixture was stirred at 60° C. for 8hours. The solvent was then evaporated in vacuo and the productcrystallized from ethanol (90% yield).

¹H NMR (400 MHz), DMSO-d₆) δ ppm 2.72-2.95 (m, 4H) 3.04-3.14 (m, 6H)4.10 (s, 3H) 4.24 (q, J 7.20 Hz, 2H) 7.46 (m, 1H).

By working according to the same method the following compounds wereprepared:

-   Ethyl    1-tert-butyl-6-[(dimethylamino)methylene]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate;-   ethyl    6-[(dimethylamino)methylene]-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz), DMSO-d₆) δ ppm 2.80 (t, J 6.34 Hz, 2H) 2.88 (t, J6.21, 2H) 3.70 (m, 2H) 4.24 (q, J 7.07 Hz, 3H) 4.58 (t, J 5.97 Hz, 2H)4.79 (bs, OH) 7.47 (bs, 1H);

-   ethyl    6-[(dimethylamino)methylene]-1-(2-ethoxy-2-oxoethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (t, J 7.07 Hz, 3H) 1.28 (t, J 7.13Hz, 3H) 2.86 (m, 4H) 3.10 (s, 6H) 4.10 (q, J 7.11 Hz, 2H) 4.26 (q, J7.11 Hz, 2H) 5.33 (s, 2H) 7.43 (s, 1H);

-   ethyl    1-[4-(aminosulfonyl)phenyl]-6-[(dimethylamino)methylene]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate;-   ethyl-6-[(dimethylamino)methylene]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J=7.07 Hz, 3H) 2.87-2.93 (m,2H) 2.95-3.00 (m, 2H) 3.12 (s, 6H) 3.83 (s, 3H) 4.32 (q, J=7.07 Hz, 2H)7.00 (d, J=9.02 Hz, 2H) 7.39 (d, J=9.02 Hz, 2H) 7.42 (s, 1H);

-   ethyl    1-(4-cyanophenyl)-6-[(dimethylamino)methylene]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.13 Hz, 3H) 2.88-2.94 (m,2H) 2.97-3.03 (m, 2H) 3.14 (s, 6H) 4.34 (q, J=7.15 Hz, 2H) 7.48 (s, 1H)7.73 (d, J=8.90 Hz, 2H) 7.96 (d, J=8.78 Hz, 2H);

-   ethyl    6-[(dimethylamino)methylene]-7-oxo-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.07 Hz, 3H) 2.87-2.93 (m,2H) 3.00 (t, J=6.71 Hz, 2H) 3.13 (s, 6H) 4.33 (q, J=7.07 Hz, 2H) 7.40(s, 1H) 7.54 (ddd, J=7.47, 4.79, 1.04 Hz, 1H) 7.56 (dt, J=8.02, 0.93 Hz,1H) 7.99-8.04 (m, 1H) 8.52 (ddd, J=4.82, 1.89, 0.85 Hz, 1H);

-   ethyl    6-(dimethylamino)methylene-1-(3,3-dimethylaminobutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate;-   ethyl    6-(dimethylamino)methylene-2-(3,3-dimethylaminobutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate;-   ethyl    6-[(dimethylamino)methylene]-7-oxo-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (t, J 7.07 Hz, 3H) 2.88 (2m, 4H)3.10 (s, 6H) 4.33 (q, J 7.07 Hz, 2H) 5.45 (q, J 8.90 Hz, 2H) 7.50 (bs,1H);

-   ethyl    6-[(dimethylamino)methylene]-7-oxo-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (t, J 7.07 Hz, 3H) 2.82 (2m, 4H)3.12 (s, 3H) 4.29 (q, J 7.07 Hz, 2H) 5.57 (q, J 9.02 Hz, 2H) 7.53 (bs,1H);

-   ethyl    6-[(dimethylamino)methylene]-7-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    1-benzyl-6-[(dimethylamino)methylene]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    6-[(dimethylamino)methylene]-1-(1-methylpiperidin-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    6-[(dimethylamino)methylene]-7-oxo-1-piperidin-4-yl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    1-(1-benzylpiperidin-4-yl)-6-[(dimethylamino)methylene]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (t, J=7.07 Hz, 3H) 1.76-2.15 (m,4H) 2.79-3.01 (m, 4H) 3.13 (s, 6H) 3.24-3.64 (m, 6H) 4.29 (q, J=7.07 Hz,2H) 5.30 (dd, J=17.01, 7.26 Hz, 1H) 7.14-7.40 (m, 6H);

-   ethyl    1-(1-acetylpiperidin-4-yl)-6-[(dimethylamino)methylene]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    6-[(dimethylamino)methylene]-1-(1-formylpiperidin-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    1-(2-dimethylaminoethyl)-6-dimethylaminomethylene-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate-   ethyl    1-(2-dimethylaminopropyl)-6-dimethylaminomethylene-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Example 8 Ethyl1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B67-X04-M00(C01)-D01]

9 g (69 mmol) ofethyl-6-[(dimethylamino)methylene]-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylatewere dissolved in 350 mL of anhydrous dimethylformamide and 13.4 g ofanhydrous potassium acetate (138 mmol) and 19.18 g (69 mmol) ofmethylisothiourea sulfate were added. The mixture was maintained at 90°C. under stirring for 8 hours. The solvent was then evaporated, theresidue redissolved with dichloromethane and washed with water. Theorganic layer was dried over Na₂SO₄ and evaporated. The crude wasfinally triturated with diethyl ether and collected by filtration togive 15.5 g (74% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t, J 7.07 Hz, 3H) 2.54 (s, 3H)2.84-3.00 (m, 4H) 4.26 (q, J 7.07 Hz, 2H) 4.31 (s, 3H) 8.53 (m, 1H).

Following the same method, but employing the suitable substitutedisothiourea derivative, the following compounds can be prepared:

-   ethyl    8-(benzylthio)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B05-X04-M00(C01)-D01];-   ethyl    1-methyl-8-(phenylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B04-X04-M00(C01)-D01].

Example 9 Ethyl8-benzyl-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B05-X06-M00(C01)-D01]

Under a nitrogen atmosphere, a 0.5 M solution of benzylzinc bromide inTHF (3.11 mL, 1.556 mmol) was added to a mixture of ethyl1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(237 mg, 0.778 mmol) and Pd(PPh₃)₄ (9 mg, 0.0078 mmol, 1%). After 20hours of heating at 60° C. under nitrogen, the mixture was cooled toroom temperature, shaken with aqueous sodium bicarbonate and ethylacetate and then filtered. The organic phase was then separated and theaqueous phase was extracted twice with ethyl acetate. The combinedorganic phase was dried over Na₂SO₄, evaporated and the crude waspurified on silica gel (eluant dichloromethane/methanol 97/3). 20 mg ofthe title compound were isolated.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, 3H) 2.99 (m, 4H) 4.23 (s, 2H)4.27 (m, 5H) 7.23 (m, 1H) 7.32 (m, 2H) 7.36 (m, 2H) 8.66 (s, 1H)

Example 10 ethyl1-methyl-8-(phenylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B04-X04-M00(C01)-D01]

To a stirred suspension of ethyl1-methyl-8-(methylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(46 mg, 0.137 mmol) and phenylthiol (16 μl, 17 mg, 0.15 mmol) in ethanol(1 mL), 1N sodium hydroxide (150 μl, 0.15 mmol) was added at roomtemperature under an argon atmosphere. After the mixture was stirred for3 days, 1N hydrochloric acid (150 μl, 0.15 mmol) was added and thesolvent removed under vacuo. By chromatography on silica gel (eluant:dichloromethane/methanol 97/3), 13 mg of ethyl1-methyl-8-(phenylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylateand 10 mg of ethyl8-ethoxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatewere isolated.

-   B04-X04-M00(C01)-D01

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (t, 3H) 2.86 (t, 2H) 2.93 (t, 2H)3.68 (s, 3H) 4.25 (q, 2H) 7.48 (m, 3H) 7.64 (m, 2H) 8.53 (s, 1H);

-   B03-X03-M00(C01)-D01

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, 3H) 1.38 (t, 3H) 2.91 (t, 2H)3.01 (t, 2H) 4.33 (m, 5H) 4.41 (q, 2H).

Example 111-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B67-X04-M00(C01)-D03]

13.00 g (0.043 mol) of ethyl1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatewere suspended in a mixture of 200 mL of methanol, 200 mL ofdimethylformamide and 200 mL of ammonium hydrate 30%. The mixture wasstirred at 65° C. in a closed bottle for about 8 hours. The solvent wasthen evaporated to dryness, the residue redissolved with dichloromethaneand washed with water. The organic layer was dried over Na₂SO₄ andevaporated. The crude was purified by chromatography on a silica gelcolumn eluted by a mixture cyclohexane/ethyl acetate, giving 6.16 g (52%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54 (s, 3H) 2.75-3.05 (m, 4H) 4.28 (s,3H) 7.47 (bs, 2H) 8.51 (m, 1H).

Example 121-methyl-8-(methylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B67-X05-M00(C01)-D03]

6.00 g (0.022 mol) of1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidewere dissolved in 1000 mL of dimethylformamide and 40.18 g of oxone wereadded. The mixture was stirred 16 hours at room temperature. Water andethyl acetate were then added and the layers separated. The organiclayer was finally dried over Na₂SO₄ and evaporated. The residue wastriturated with diethyl ether and 5.40 g (80% yield) of the titlecompound were collected by filtration.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.06 (m, 4H) 3.43 (s, 3H) 4.29 (s, 3H)7.45 (bs, 2H) 8.91 (m, 1H).

By working according to this methodology the following compound wasprepared:

-   ethyl    1-methyl-8-(methylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B67-X05-M00(C01)-D01]

Example 138-(cyclohexylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B27-X00-M00(C01)-D03] and8-(cyclohexylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B27-X00-M01(C01)-D03]

1.5 g of1-methyl-8-(methylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidewere dissolved in 100 mL of dry dimethylsulfoxide and 1.15 mL ofcyclohexylamine were added. After 16 hours at 80° C. under nitrogen thesolvent was evaporated at reduced pressure. The residue was thenredissolved with dichloromethane and washed with water. The organiclayer was dried over Na₂SO₄ and evaporated to dryness. By chromatographyon a silica gel column (eluant dichloromethane/acetone 9/1) 300 mg of8-(cyclohexylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamideand 200 mg of8-(cyclohexylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamideand were obtained (30% yield overall).

-   B27-X00-M00(C01)-D03

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63 (m, 10H) 2.73 (m, 2H) 2.94 (m, 2H)3.69 (m, 1H) 4.31 (m, 3H) 6.94 (d, J 6.58 Hz, 1H) 7.23 (s, 1H) 7.43 (s,1H) 8.20 (s, 1H);

-   B27-X00-M01(C01)-D03

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63 (m, 10H) 3.88 (m, 1H) 4.66 (s, 3H)7.40 (s, 1H) 7.47 (d, J 8.66 Hz, 1H) 7.59 (s, 1H) 7.74 (s, 1H) 7.87 (d,J 8.66 Hz, 1H) 9.13 (s, 1H)

By working according to this methodology, and by taking into accountthat when the amine is available as a salt, stoichiometric amounts ofpotassium carbonate were employed, the following compounds were preparedas coded in Table VI:

TABLE VI B76-X06-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (m, 6H) 2.75 (m, 2 H) 2.96 (m, 2 H) 3.76 (m, 4 H) 4.29 (s, 3 H) 7.24 (s, 1 H)7.44 (s, 1 H) 8.29 (s, 1 H) B23-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSOd₆) δ ppm 2.21 (s, 6 H) 2.46 (m,, 2 H) 2.74 (m, 2 H) 2.95 (m,, 2 H)3.41 (m, 2 H) 4.32 (s, 3 H) 6.90 (t, J 5.73 Hz, 1 H) 7.24 (s, 1 H) 7.43(s, 1 H) 8.21 (s, 1 H) B24-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.69 (m, 4 H); 2.49 (m, 4 H); 2.95 and 2.61 (2m, 4 H); 3.40 (m, 2H); 4.32 (s, 3 H); 6.95 (bs, NH); 7.2-7.4 (2s, 2 H); 8.21 (s, 1 H).B25-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (m, 6 H) 2.52(m, 6 H) 2.70 (m, 2 H,) 2.95 (m, 2 H,) 3.42 (m, 2 H) 4.32 (s, 3 H)7.2-7.4 (2s, 2 H) 8.21 (s, 1 H). B26-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.37-2.54 (m, 6 H) 2.74 (m, 2 H,) 2.95 (m, 2 H.) 3.45 (m,2 H) 3.59 (m, 4 H) 4.32 (s, 3 H) 6.93 (bs, NH) 8.22 (s, 1 H).B28-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (m, 11 H) 2.72(m, 2 H) 2.94 (m, 2 H,) 3.16 (m, 2 H) 4.31 (s, 3 H) 7.14-7.49 (3bs, 3 H)8.19 (s, 1 H). B29-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00(m, 3 H) 2.60-3.20 (m, 10H) 2.73 (m, 2 H) 2.95 (m, 2 H) 3.88 (m, 1 H)4.31 (s, 3 H) 6.88 (bs, 1 H) 7.24 (s, 1 H) 7.43 (s, 1 H) 8.22 (s, 1 H).B30-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.98 (m, 2 H) 3.07(m, 2 H) 4.34 (s, 3 H) 6.60 (m, 2 H) 7.44 (m, 2 H) 7.32 (s, 1 H) 8.71(s, 1 H). B31-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74 (m,2 H) 2.94 (m, 2 H) 4.62 (d, J 6.10 Hz, 2 H) 7.23 (m, 2 H) 7.34 (m, 1 H)7.41 (s, 1 H) 7.73 (m, 2 H) 8.24 (s, 1 H) 8.50 (m, 1 H).B32-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.86 (m, 4 H) 4.17(s, 3 H) 4.56 (d, J 6.22 Hz, 2 H) 7.23 (s, 1 H) 7.34 (dd, J 7.87, 4.69Hz, 1 H) 7.42 (s, 1 H) 7.74 (m, 1 H) 7.74 (dt, J 7.68, 1.83 Hz, 1 H)8.24 (s, 1 H) 8.44 (dd, J 4.76, 1.46 Hz, 1 H) 8.57 (d, J 1.83 Hz, 1 H)B33-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.73 (m, 2 H) 2.93(m, 2 H) 4.55 (d, J 6.22 Hz, 2 H) 7.22 (s, 1 H) 7.32 (m, 2 H) 7.41 (s, 1H) 7.78 (bs, 1 H) 8.24 (s, 1 H) 8.49 (m, 2 H). B34-X00-M00(C01)-D03 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.73 (m, 2 H) 2.94 (m, 2 H) 4.62 (d, J 6.22Hz, 2 H) 7.23 (s, 1 H) 7.41 (s, 1 H) 7.54-7.76 (2m, 4 H) 7.82 (bs. 1 H)8.24 (s, 1 H). B35-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74(m, 2 H) 2.94 (m, 2 H) 4.23 (s, 3 H) 4.44 (d, J 6.22 Hz, 2 H) 5.97 (s, 2H) 6.83 (m, 2 H) 6.91 (s, 1 H) 7.23 (s, 1 H); 7.42 (s, 1 H) 7.63 (bs, 1H) 8.23 (s, 1 H). B37-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.73 (m, 2 H) 1.93 (m, 2 H) 2.22 (m, 2 H) 2.73 (m, 2 H) 2.95 (m, 2 H)3.34 (m, 4 H) 4.32 (s, 3 H) 7.09 (bs, 1 H) 7.22 (s, 1 H) 7.43 (s, 1 H)8.22 (s, 1 H). B38-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74(m, 2 H) 2.81 (t, J 7.38 Hz, 2 H) 2.95 (t, J 7.62 Hz, 2 H) 3.54 (m, 2 H)4.32 (s, 3 H) 6.86 (s, 1 H) 7.16 (t, J 5.55 Hz, 1 H) 7.24 (s, 1 H) 7.43(s, 1 H) 7.61 (s, 1 H) 8.22 (s, 1 H) 12.00 (s, 1 H) B39-X00-M00(C01)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.00 (m, 2 H) 2.73 (m, 2 H) 2.94 (m, 2H) 3.33 (m, 4 H) 4.25 (s, 3 H) 6.99 (s, 1 H) 7.27 (m, 3 H) 7.24 (s, 3 H)7.43 (s, 1 H) 7.80 (s, 1 H) 8.22 (s, 1 H). B40-X00-M00(C01)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.22 (s, 3 H) 2.44 (m, J 4.39 Hz, 4 H) 2.83 (m,4 H) 3.10 (m, 4 H) 4.20 (s, 3 H) 4.47 (d, J 6.22 Hz, 2 H) 6.78 (m, 2 H)6.94 (m, 1 H) 7.13 (m, 1 H) 7.22 (s, 1 H) 7.41 (s, 1 H) 7.63 (s, 1 H)8.22 (s, 1 H) B41-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28(s, 3 H) 2.52 (m, 4 H) 2.83 (m, 4 H) 3.11 (s, 4 H) 4.22 (s, 3 H) 4.43(d, J 6.22 Hz, 2 H) 6.88 (d, J 8.78 Hz, 2 H) 7.20 (d, J 8.66 Hz, 2 H)7.23 (s, 1 H) 7.41 (t, 1 H) 7.57 (t, J 6.10 Hz, 1 H) 8.21 (s, 1 H)B42-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.75 (m, 2 H) 2.95(m, 2 H) 4.27 (s, 3 H) 4.71 (d, J 6.22 Hz, 2 H) 6.96 (m, 1 H) 7.32 (m, 1H) 7.24 (s, 1 H) 7.43 (s, 1 H) 7.73 (s, 1 H) 8.26 (s, 1 H).B44-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85 (m, 4 H) 4.27(s, 3 H) 4.52 (d, J 5.97 Hz, 2 H) 6.24 (d, J 2.68 Hz, 1 H) 6.38 (dd, J3.11, 1.89 Hz, 1 H) 7.23 (m, J 0.49 Hz, 1 H) 7.43 (s, 1 H) 7.56 (m, J0.98 Hz, 2 H) 8.24 (s, 1 H) B45-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.5-1.9 (3m, 4 H) 2.73 (m, 2 H) 2.94 (m, 2 H) 3.33 (m, 2H) 3.6-3.8 (2m, 2 H) 4.05 (m, 1 H) 4.31 (s, 3 H) 7.10 (bs, 1 H) 7.24 (s,1 H) 7.44 (s, 1 H) 8.21 (s, 1 H). B46-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.73 (t, J = 7.62 Hz, 2 H) 2.93 (t, J = 7.68 Hz, 2 H)3.73 (s, 3 H) 4.19 (s, 3 H) 4.51 (d, J = 6.34 Hz, 2 H) 6.74-6.82 (m, 1H) 6.87-6.96 (m, 2 H) 7.16-7.30 (m, 2 H) 7.41 (s, 1 H) 7.68 (t, J = 6.65Hz, 1 H) 8.23 (s, 1 H) B47-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.68 (none, 2 H) 2.81 (m, 4 H) 3.10 (none, 1 H) 4.34 (s, 3 H) 7.00(s, 1 H) 7.23 (s, 1 H) 7.43 (s, 1 H) 8.18 (s, 1 H) B48-X00-M01(C01)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72 (s, 6 H) 2.14 (s, 3 H) 2.22 (m, J2.07 Hz, 6 H) 4.70 (s, 3 H) 7.19 (s, 1 H) 7.41 (s, 1 H) 7.48 (d, J 8.66Hz, 1 H) 7.76 (s, 1 H) 7.91 (d, J 8.66 Hz, 1 H) 9.13 (s, 1 H)B49-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99 (s, 3 H) 1.04(d, J 7.07 Hz, 3 H) 1.19 (s, 3 H) 1.4-2.4 (5m, 8H) 2.70-3.00 (2t, 4 H)3.34 (bs, 2 H) 4.35 (s, 3 H) 7.23-7.42 (3bs, 3 H) 8.20 (s, 1 H)B50-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (m, 2 H) 1.91(d, J 11.71 Hz, 2 H) 2.06 (m, 2 H) 2.73 (m, J 7.93, 7.44 Hz, 2 H) 2.83(d, J 11.34 Hz, 2 H) 2.94 (t, J 7.62 Hz, 2 H) 3.48 (s, 2 H) 3.70 (m, 1H) 4.30 (s, 3 H) 7.01 (d, J 4.51 Hz, 1 H) 7.23 (s, 1 H) 7.30 (m, 5 H)7.43 (s, 1 H) 8.20 (s, 1 H) B51-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.73 (t, J = 7.62 Hz, 2 H) 2.93 (t, J = 7.68 Hz, 2 H)4.10 (s, 3 H) 4.60 (d, J = 6.10 Hz, 2 H) 7.22 (s, 1 H) 7.27 (s, 2 H)7.41 (s, 1 H) 7.51 (d, J = 8.54 Hz, 2 H) 7.77 (d, J = 8.41 Hz, 2 H)7.78-7.83 (m, 1 H) 8.23 (s, 1 H) B52-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.73 (m, 2 H) 2.93 (m, 2 H) 3.18 (s, 3 H) 4.63 (d, J 6.22Hz, 2 H) 7.23 (s, 1 H) 7.41 (s, 1 H) 7.59 (m, 2 H) 7.86 (m, 3 H) 8.24(s, 1 H). B53-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.11 (m,4 H) 4.37 (s, 3 H) 4.43 (s, 3 H) 7.37 (m, 4 H) 7.57 (s, 1 H) 7.74 (m, 2H) 8.20 (m, 2 H) 8.92 (s, 1 H). B54-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.73 and 2.93 (2t, 4 H, J 8.04 Hz) 4.18 (s, 3 H) 4.49 (d,2 H, 6.34 Hz) 7.13 (m, 1 H) 7.36 (m, 1 H) 7.42 and 7.23 (2s, 2 H) 7.58(m, 1 H) 7.73 (bs, 2 H) 8.23 (s, 1 H). B55-X00-M00(C01)-D03 ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.24 (m, 2 H) 0.44 (m, 2 H) 1.13 (m, 1 H) 2.74 (m, 2H) 2.95 (t, J 7.68 Hz, 2 H) 3.20 (m, 2 H) 4.32 (s, 3 H) 7.17 (t, J 5.79Hz, 1 H) 7.23 (s, 1 H) 7.43 (s, 1 H) 8.21 (s, 1 H) B56-X00-M00(C01)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.75 (t, J = 7.68 Hz, 2 H) 2.95 (t, J =7.80 Hz, 2 H) 3.51-3.75 (m, 2 H) 4.04 (dd, J = 11.52, 6.77 Hz, 1 H) 4.27(s, 3 H) 4.34 (dd, J = 11.58, 2.19 Hz, 1 H) 4.38-4.48 (m, 1 H) 6.74-6.94(m, 4 H) 7.24 (s, 1 H) 7.36 (t, J = 5.97 Hz, 1 H) 7.44 (s, 1 H) 8.25 (s,1 H) B57-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74 (m, 2 H)2.94 (m, 2 H) 4.14 (bs, 3 H) 4.62 (d,, J 6.22 Hz2 H) 7.23 (s, 1 H) 7.42(s, 1 H) 7.51 (m, 2 H) 7.60 (m, 1 H) 7.83 (bs, 1 H) 9.26 (s, 1 H).B58-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74 (m, 2 H) 2.95(m, 2 H) 3.05 (m, 2 H) 3.69 (m, 2 H) 4.33 (s, 3 H) 7.24 (3m, 3 H) 7.32(m, 1 H), 7.43/m, 1 H) 8.22 (s, 1 H) 8.51 (m, 1 H). B59-X00-M00(C01)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.73 and 2.93 (2t, 4 H, J 7.56) 4.18 (s,3 H) 6.27 (2s, 2 H) 7.22 (m, 1 H) 7.31 (2s, 2 H) 7.37-7.43 (2m, 2 H)7.55 (s, 1 H) 7.74 (bs, 1 H) 8.24 (s, 1 H). B30-X00-M01(C01)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 4.72 (s, 3 H) 6.67 (m, 1 H) 7.56 (m, 1 H) 7.44(s, 1 H) 7.63 (s, 1 H) 8.33 (m, 1 H) 8.35 (m, 1 H) 9.73).B45-X00-M01(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50-2.00 (2m, 4 H)3.34 (m, 2 H) 3.67-3.69 (2m, 2 H) 4.18 (m, 1 H) 4.67 (s, 3 H) 7.42 (m, 1H) 7.74 (m, 2 H) 7.88 (m, 1 H) 7.88 (m, 1 H) 9.15 (s, 1 H).B28-X00-M01(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-2.00 (6m, 11H) 3.34 (m, 2 H) 4.67 (s, 3 H) 7.41 (bs, 1 H) 7.48 (m, 2 H) 7.86 (m, 1H) 9.12 (s, 1 H). B29-X00-M01(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm4.04 (m, 1 H) 4.66 (s, 3 H) 7.42 (bs, 1 H) 7.50 (m, 1 H) 7.70 (s, 1 H)7.88 (m, 1 H) 9.15 (s, 1 H). B50-X00-M01(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.65 (s, 3 H) 7.00-8.00 (m, 9H) 9.14 (s, 1 H).B55-X00-M01(C01)-D03 ¹H NMR (400 MHz, DMSOd₆) δ ppm 0.31 (m, 2 H) 0.49(m, 2 H) 1.25 (m, 1 H) 3.33 (m, 2 H) 4.68 (s, 3 H) 7.41 (s, 1 H) 7.49(m, 2 H) 7.73 (s, 1 H) 7.75 (s, 1 H) 9.14 (s, 1 H). B01-X00-M00(C01)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84 (m, 4 H) 3.40 (m, 4 H) 4.31 (s, 3H) 4.66 (s, 1 H) 6.96 (t, J 5.67 Hz, 1 H) 7.23 (s, 1 H) 7.43 (s, 1 H)8.21 (s, 1 H) B02-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72(m, 2 H) 2.73 (m, 2 H) 2.95 (m, 2 H) 3.50 (m, 2 H) 4.32 (s, 3 H) 4.45(m, 1 H) 7.05 (bs, 1 H) 7.23 (s, 1 H) 7.42 (s, 1 H) 8.20 (s, 1 H).B05-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.73 (m, 2 H) 2.93(m, 2 H) 4.17 (bs, 3 H) 4.55 (d, J 6.22 Hz, 2 H) 7.15-7.40 (m, 7H) 7.70(bs, 1 H) 8.23 (s, 1 H). B69-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.15 (s, 3 H) 2.74 (t, J = 7.68 Hz, 2 H) 2.95 (t, J = 7.68 Hz, 2H) 3.44 (s, 3 H) 4.32 (s, 3 H) 4.46 (d, J = 5.73 Hz, 2 H) 5.66 (dd, J =3.41, 0.73 Hz, 1 H) 5.84 (d, J = 3.29 Hz, 1 H) 7.24 (s, 1 H) 7.28 (t, J= 4.94 Hz, 1 H) 7.43 (s, 1 H) 8.24 (s, 1 H) B70-X00-M00(C01)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.75 and 2.95 (2t, 4 H, J 7.32 Hz) 4.24 (s, 3H) 4.57 (d, 2 H, J 6.22 Hz) 6.13 (s, 1 H) 7.23 and 7.43 (2s, 2 H) 7.64(bs, 1 H) 8.25 (s, 1 H) B71-X00-M00(C01)-D03 B72-X00-M00(C01)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.74 (t, J = 7.62 Hz, 2 H) 2.94 (t, J = 7.62Hz, 2 H) 4.20 (s, 3 H) 4.58 (d, J = 6.22 Hz, 2 H) 6.53 (dd, J = 2.50,1.77 Hz, 1 H) 7.22 (s, 1 H) 7.41 (s, 1 H) 7.46 (d, J = 8.66 Hz, 2 H)7.72 (dd, J = 1.71, 0.49 Hz, 1 H) 7.74-7.77 (m, 1 H) 7.77 (d, J = 8.66Hz, 2 H) 8.24 (s, 1 H) 8.43 (dd, J = 2.50, 0.55 Hz, 1 H)B74-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.73 (m, 2 H) 2.96(m, 2 H) 3.16 (s, 6 H) 4.43 (s, 3 H) 7.23 (bs, 1 H) 7.43 (bs, 1 H) 8.28(s, 1 H).

Example 14 Ethyl6-[(dimethylamino)methylene]-1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Step 1. 3-methoxy-5,5-dimethyl-cyclohex-2-enone

A solution of 5,5-dimethyl-cyclohexane-1,3-dione (80.0 g, 0.57 mol) inanhydrous methanol (600 mL) was treated with a 1 M solution of titaniumchloride (TiCl₄) in dichloromethane (17.2 mL) After stirring 1 hour atroom temperature, the mixture was slowly poured into cold 5% NaHCO₃solution and extracted with diethyl ether (450 mL×6). The organic layerswere collected, washed with brine, dried on Na₂SO₄ and evaporated todryness affording the title compound (81.5 g, 92% yield) as a paleyellow oil.

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.05 (s, 6H) 2.19 (s, 2H) 2.26 (s, 2H)3.68 (s, 3H) 5.35 (s, 1H).

Step 2. 5,5-dimethyl-cyclohex-2-enone

A solution of 3-methoxy-5,5-dimethyl-cyclohex-2-enone (80 g, 0.52 mol)in anhydrous tetrahydrofuran (270 mL) was treated dropwise with a 1 Msolution of LiAlH₄ in tetrahydrofuran (182 mL), under argon atmosphereand keeping the temperature of the reaction between 0° C. and 5° C. Thetemperature was allowed to rise to 25° C. and the mixture was stirredfor 4 hours. The resulting slurry was cooled with an ice bath, quenchedwith ethyl acetate (30 mL) and poured with caution into a cooled 2 MH₂SO₄ solution. The aqueous solution was then extracted with diethylether (300 mL×3), dried on Na₂SO₄ and evaporated under reduced pressureto remove most of the solvent. The crude material contained the titlecompound as a low boiling point oil that was used in the next stepwithout further purification.

¹H NMR (300 MHz, CHCL₃-d) δ ppm 1.04 (s, 6H) 2.23 (dd, J 4.10, 2.05 Hz,2H) 2.27 (s, 2H) 6.02 (dt, J 9.96, 2.05 Hz, 1H) 6.85 (dt, J 9.96, 4.10Hz, 1H).

Step 3. 4,4-dimethyl-7-oxa-bicyclo[4.1.0]heptan-2-one

5,5-dimethyl-cyclohex-2-enone from the previous step (0.52 moltheoretically) was dissolved in methanol (500 mL), cooled to 0° C. andtreated with 30% hydrogen peroxide (265 mL, 2.6 mol). The resultingsolution was treated dropwise with a 2% NaOH solution (142 mL, 0.067mol) keeping the reaction temperature around 0° C. The mixture wasallowed to stay at 4° C. for twenty hours and was then diluted withwater (900 mL) and extracted with ethyl ether (450 mL×4).

The extracts were collected, washed with 5% Na₂S₂O₅ solution, withbrine, dried on Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by distillation under vacuum to obtain the titlecompound (56.8 g, 78.3% yield) as a colourless oil.

¹H NMR (300 MHz, CHCl₃-d) δ ppm 0.91 (s, 3H) 1.01 (s, 3H) 1.82 (m, 2H)2.03 (d, J 15.53 Hz, 1H) 2.64 (d, J 13.77 Hz, 1H) 3.20 (dt, J 3.74, 0.92Hz, 1H) 3.49 (t, J 4.10 Hz, 1H).

Step 4. 2-methoxy-5,5-dimethyl-cyclohex-2-enone

A solution of 4,4-dimethyl-7-oxa-bicyclo[4.1.0]heptan-2-one (44.0 g,0.31 mol) in methanol (150 mL) was added to a solution of 85% potassiumhydroxide (20.7 g, 0.31 mol) in methanol (450 mL) at room temperature.The mixture was kept at this temperature for 20 hours and was thenheated to reflux for 30 minutes. After cooling, the solution was dilutedwith water (1.2 L) and extracted with ethyl ether (350 mL×5). Theorganic extracts were collected, washed with brine, dried on Na₂SO₄ andevaporated under vacuum to remove most of the solvent. The crudematerial was purified by distillation to obtain pure the title compound(32.8 g, 68% yield) as an oil.

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.04 (s, 6H) 2.30 (d, J 4.69 Hz, 2H)2.35 (s, 2H) 3.59 (t, 3H) 5.67 (t, J 4.54 Hz, 1H).

Step 5. Ethyl(3-methoxy-6,6-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate

60% sodium hydride in mineral oil (2.41 g, 60.3 mmol) was suspended inanhydrous tetrahydrofuran (60 mL) under argon atmosphere and treatedwith a solution of 2-methoxy-5,5-dimethyl-cyclohex-2-enone (6.20 g, 40.2mmol) in anhydrous tetrahydrofuran (50 mL). After 15 minutes, a solutionof diethyl oxalate (8.17 mL, 60.3 mmol) in anhydrous tetrahydrofuran (50mL) was added and the mixture was refluxed for 1 hour. The slurry wasdiluted with water (800 mL), acidified with 1 N HCl (50 mL) andextracted with ethyl acetate (500 mL×2). The organic layers werecollected, washed with brine, dried on Na₂SO₄ and evaporated to drynessto obtain the crude title compound (10.60 g) as an orange oil, which wasused without further purification.

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.41 (t, 3H) 2.77 (s, 2H) 3.13 (s, 6H)4.23 (s, 3H) 4.40 (q, J 7.13 Hz, 2H) 7.58 (s, 1H).

Step 6. Ethyl1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

A solution of ethyl(3-methoxy-6,6-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate from theprevious step (40.2 mmol theoretically) in acetic acid (65 mL) wastreated dropwise with a solution of methyl hydrazine (2.14 mL, 40.2mmol) in acetic acid (20 mL) and allowed to stand at room temperatureovernight. The mixture was then diluted with water (800 mL) andextracted with ethyl acetate (500 mL×2). The organic extracts werewashed with brine, dried on Na₂SO₄ and evaporated to dryness. The crudematerial was chromatographed on silica gel eluted withdichloromethane/ethyl acetate 100:5 to obtain the pure title compound(4.8 g, 47.7% yield).

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.42 (t, J 7.18 Hz, 3H) 1.49 (s, 3H)1.98 (t, J 6.45 Hz, 2H) 2.61 (t, J 6.45 Hz, 2H) 4.19 (s, 3H) 4.43 (q, J7.03 Hz, 2H)

Step 7. Ethyl6-[(dimethylamino)methylene]-1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

A solution of ethyl1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (4.8g, 19.18 mmol) in anhydrous dimethylformamide (30 mL) was treated withdimethylformamide di-tert-butylacetal (9.19 mL, 38.35 mmol) at 65° C.for 2 hours. The mixture was evaporated to dryness and the crudematerial was crystallized from hexane to give the title compound (5.1 g,87% yield).

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.21 (m, 9H) 2.76 (s, 2H) 3.15 (s, 6H)4.22 (s, 3H) 4.41 (q, 2H).

Example 15 Ethyl6-(hydroxymethylene)-1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Step 1. 5,5-dimethyl-7-oxabicyclo[4.1.0]heptan-2-one

A solution of 4,4-dimethyl-cyclohex-2-enone (32.0 g, 0.26 mol) and 30%hydrogen peroxide (132 mL, 1.29 mol) in methanol (250 mL) was treateddropwise with a 2% sodium hydroxide solution (70 mL, 0.035 mol) keepingthe reaction temperature around 0° C. The mixture was allowed to stay at4° C. for 20 hours and was then diluted with water (400 mL) andextracted with diethyl ether (250 mL×4).

The extracts were collected, washed with 5% Na₂S₂O₅ solution, withbrine, dried on Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by distillation under vacuum to obtain the titlecompound (27.6 g, 76.4% yield) as an oil.

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.05 (s, 3H) 1.21 (s, 3H) 1.20-2.50 (m,5H) 3.20 (m, 1H).

Step 2. 2-methoxy-4,4-dimethylcyclohex-2-en-1-one

A solution of 5,5-dimethyl-7-oxabicyclo[4.1.0]heptan-2-one (19.4 g,138.4 mmol) in methanol (95 mL) was added to a solution of 85% potassiumhydroxide (9.1 g, 138.4 mmol) in methanol (285 mL) at room temperature.The mixture was kept at this temperature for 20 hours and was thenheated to reflux for 30 minutes. After cooling, the solution was dilutedwith water (750 mL) and extracted with diethyl ether (350 mL×4). Theorganic extracts were collected, washed with brine, dried on Na₂SO₄ andevaporated to dryness. The crude material was taken up with hexane (380mL), maintained under vigorous stirring for 30 minutes and filtered toremove the solid material. The filtrate was evaporated under vacuum toobtain the pure title compound (9.8 g, 45.9% yield) as a pale yellowoil.

¹H NMR (CDCl₃ 400 MHz) δ ppm 1.23 (s, 6H) 1.87 (t, 2H) 2.61 (t, 2H) 3.60(s, 3H) 5.57 (s, 1H)

Step 3. Ethyl(3-methoxy-5,5-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate

A solution of 2-methoxy-4,4-dimethyl-cyclohex-2-enone (12.5 g, 81.1mmol) and diethyl oxalate (12.1 mL, 89.2 mmol) in ethyl ether wastreated with a 1 M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran under argon atmosphere. The reaction was stirred at roomtemperature for 2 hours, poured into a 10% NaH₂PO₄ solution (500 mL) andextracted with diethyl ether (300 mL×2). The organic extracts werewashed with brine, dried on Na₂SO₄ and evaporated to dryness. The crudematerial was taken up with hexane, stirred and filtered to give thetitle compound (16.8 g, 81.5% yield) as a yellow crystalline solid.

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.15 (s, 6H) 1.38 (t, 3H) 2.77 (s, 2H)3.63 (s, 3H) 4.35 (q, 2H) 5.62 (s, 1H).

Step 4. Ethyl1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

A solution of ethyl(3-methoxy-5,5-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate (15.50 g,0.061 mol) in acetic acid (100 mL) was treated dropwise with a solutionof methyl hydrazine (3.49 mL, 0.066 mol) dissolved in acetic acid (50mL). After 24 hours at room temperature, the reaction mixture wasdiluted with water (2 L) under vigorous stirring. The resultingprecipitate was filtered and washed with water to obtain the titlecompound (10.30 g, 67.6% yield) as a yellow solid.

¹H NMR (300 MHz, CHCl₃-d) δ ppm 1.20 (s, 6H) 1.42 (t, 3H) 2.43 (s, 2H)2.93 (s, 2H) 4.21 (s, 3H) 4.41 (q, 2H).

Step 5. Ethyl6-(hydroxymethylene)-1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

A solution of ethyl1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (1.00g, 4 mmol) in anhydrous ethyl formate (10 mL) was treated with sodiumethoxide (0.54 g, 8 mmol) and refluxed for 3 hours. The mixture wascooled to room temperature and poured into cold water (40 mL). Theaqueous layer was washed with diethyl ether (40 mL) to remove unreactedstarting material, acidified with a 20% NaH₂PO₄ solution and extractedwith ethyl acetate (50 mL×2). The organic extracts were collected, driedon Na₂SO₄ and evaporated to dryness to obtain the title compound (0.88g, 78.8% yield) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (s, 6H) 1.32 (t, 3H) 2.87 (s, 2H)4.19 (s, 3H) 4.30 (q, 2H) 7.74 (s, 1H) 14.00 (br, 1H)

Example 16 Ethyl8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B00-X00-M00(C01)-D01]

16.00 g (0.06 mol) ofethyl-6-[(dimethylamino)methylene]-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylatewere dissolved in 600 mL of ethanol and 3.90 g of sodium ethylate, and5.44 g of guanidine hydrochloride were added consecutively. The solutionwas stirred at reflux for 12 hours. The solvent was then evaporated, theresidue redissolved with dichloromethane and washed with water. Theorganic layer was then dried over anhydrous Na₂SO₄ and concentrated. Theresidue was triturated with diethyl ether and the product collected byfiltration (85% yield as a white solid).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.28 (t, J 7.07 Hz, 3H) 2.68-2.93 (m,4H) 4.25 (q, J 7.07 Hz, 2H) 4.30 (s, 3H) 6.54 (bs, 2H) 8.15 (m, 1H).

According to this same methodology, but employing a suitable substitutedguanidine derivative, the following compounds were prepared, as reportedin table VII:

TABLE VII B04-X00-M00(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t,J 7.07 Hz, 3 H) 2.82 (m, 2 H) 2.95 (m, 2 H) 4.27 (q, J 7.07 Hz, 2 H)4.32 (s, 3 H) 6.93 (m, 2 H) 7.37 (m, 2 H) 7.77 (m, 2 H) 8.39 (s, 1 H)9.49 (s, 1 H). B06-X00-M00(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29(t, J 7.07 Hz, 3 H) 2.84 (m, 2 H) 2.96 (m, 2 H) 4.27 (q, J 7.07 Hz, 2 H)6.97 (m, 1 H) 7.30 (m, 1 H) 7.54 (m, 1 H) 7.97 (m, 1 H) 8.42 (s, 1 H)9.74 (s, 1 H). B07-X00-M00(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29(t, J 7.07 Hz, 3 H) 2.85 (m, 2 H) 2.97 (m, 2 H) 4.28 (q, J 7.07 Hz, 2 H)4.33 (s, 3 H) 7.28 (m, 1 H) 7.51 (m, 1 H) 7.89 (m, 2 H) 8.18 (bs, 1 H)8.47 (s, 1 H) 9.88 (s, 1 H). B08-X00-M00(C01)-D01 B09-X00-M00(C01)-D01¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t, J 7.07 Hz, 3 H) 2.21 (s, 3 H,)2.45 (m, 2 H) 2.81 (m, 2 H) 2.95 (m, 2 H) 3.69 (m, 4 H) 4.26 (q, J 7.07Hz, 2 H) 4.33 (s, 3 H) 6.65 (m, 1 H) 7.10 (m, 1 H) 7.19 (m, 1 H) 7.21(m, 1 H) 8.38 (s, 1 H) 9.31 (bs, 1 H). B10-X00-M00(C01)-D01 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.34 (t, J = 7.19 Hz, 3 H) 2.25 (s, 3 H) 2.48 (m, 4H) 2.84 (t, J = 7.74 Hz, 2 H) 2.99 (t, J = 7.74 Hz, 2 H) 3.10 (m, 4 H)4.32 (q, J = 7.19 Hz, 2 H) 4.36 (s, 3 H) 6.93 (d, J = 9.34 Hz, 2 H) 7.53(d, J = 9.34 Hz, 2 H) 8.37 (s, 1 H) 9.29 (s, 1 H) B04-X00-M00(C02)-D01B04-X00-M00(C04)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (t, J 7.07 Hz,3 H) 2.82 (m, 2 H) 2.96 (m, 2 H) 3.79 (m, 2 H) 4.28 (q, J 7.07 Hz, 2 H)4.78 (t, J 5.25 Hz, OH) 4.88 (t, J 5.73 Hz, 2 H) 6.95 (m, 1 H) 7.29 (m,2 H) 7.65 (m, 2 H) 8.39 (s, 1 H) 9.44 (bs, 1 H). B04-X00-M00(C06)-D01 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.12 (t, 3 H, J = 7.07 Hz) 1.33 (t, 3 H, J= 7.07 Hz) 2.90 (m, 2 H) 3.03 (m, 2 H) 4.07 (q, 2 H, J = 7.07 Hz) 4.31(q, 2 H, J = 7.07 Hz) 5.73 (s, 2 H) 7.01 (m, 1 H) 7.31 (m, 2 H) 7.57 (m,2 H) 8.44 (s, 1 H) 9.49 (bs, 1 H). B04-X00-M00(C08)-D01B04-X00-M00(C09)-D01 B04-X00-M00(C10)-D01 B04-X00-M00(C05)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.33 (t, J 7.07 Hz, 3 H) 2.87 (m, 2 H) 3.02 (m,2 H) 4.36 (q, J 7.07 Hz, 2 H) 5.53 (q, J 8.90 H, 2 H) 6.90 (m, 1 H) 7.24(m, 2 H) 7.79 (m, 2 H) 8.42 (s, 1 H) 9.74 (bs, 1 H).B04-X00-M04(C05)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (t, J 7.07 Hz,3 H) 2.87 (m, 2 H) 2.98 (m, 2 H) 4.29 (q, J 7.07 Hz, 2 H) 5.85 (q, J8.90 Hz, 2 H) 6.80-7.60 (3m, 5 H) 8.43 (s, 1 H) 9.58 (bs, 1 H).B04-X00-M00(C11)-D01 B36-X00-M00(C01)-D01 B12-X00-M00(C01)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.33 (t, J 7.07 Hz, 3 H) 2.25 (s, 3 H) 2.52 (m,4 H) 2.93 (m, 8 H) 4.31 (q, J 7.07 Hz, 2 H) 4.36 (s, 3 H) 7.54 (d, J8.90 Hz, 1 H) 7.93 (dd, J 8.84, 2.50 Hz, 1 H) 8.07 (d, J 2.56 Hz, 1 H)8.46 (s, 1 H) 9.78 (s, 1 H) B13-X00-M00(C01)-D01 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33 (t, J 7.07 Hz, 3 H) 2.28 (s, 3 H) 2.53 (m, 4 H) 2.94(m, 8 H) 4.31 (q, J 7.15 Hz, 2 H) 4.38 (s, 3 H) 7.14 (d, J 8.90 Hz, 1 H)7.53 (dd, J 8.72, 2.50 Hz, 1 H) 7.96 (d, J 2.44 Hz, 1 H) 8.44 (s, 1 H)9.60 (s, 1 H) B00-X00-M00(C00)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33(t, J = 7.2 Hz, 3 H) 2.78 (m, 2 H) 2.96 (m, 2 H) 4.31 (q, J = 7.2 Hz, 2H) 6.64 (m, 2 H) 8.19 (bs, 1 H) B00-X00-M00(C03)-D01B00-X00-M04(C03)-D01 B00-X00-M00(C04)-D01 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.32 (t, J = 7.07 Hz, 3 H) 2.76 (t, J = 7.68 Hz, 2 H) 2.94 (t, J =7.50 Hz, 2 H) 3.79-3.88 (m, 2 H) 4.30 (q, J = 7.07 Hz, 2 H) 4.80 (t, J =5.79 Hz, 1 H) 4.84 (t, J = 5.97 Hz, 2 H) 6.55 (s, 2 H) 8.19 (s, 1 H)B00-X00-M00(C05)-D01 B00-X00-M00(C08)-D01 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.35 (t, J = 7.07 Hz, 3 H) 2.83 (t, J = 7.56 Hz, 2 H) 3.02 (t, J =7.38 Hz, 2 H) 4.36 (q, J = 7.07 Hz, 2 H) 6.14 (s, 2 H) 7.44 (s, 2 H)7.83 (d, J = 8.78 Hz, 2 H) 7.92-7.99 (m, 2 H) 8.25 (s, 1 H)B00-X00-M00(C09)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, J = 7.13Hz, 3 H) 2.80 (t, J = 7.50 Hz, 2 H) 3.00 (t, J = 7.38 Hz, 2 H) 3.85 (s,3 H) 4.34 (q, J = 7.11 Hz, 2 H) 6.10 (s, 2 H) 7.03 (d, J = 9.02 Hz, 2 H)7.50 (d, J = 9.02 Hz, 2 H) 8.20 (s, 1 H) B00-X00-M00(C10)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.34 (t, J = 7.07 Hz, 3 H) 2.83 (t, J = 7.56Hz, 2 H) 3.01 (t, J = 7.68 Hz, 2 H) 4.36 (q, J = 7.15 Hz, 2 H) 6.24 (s,2 H) 7.83 (d, J = 8.78 Hz, 2 H) 7.97 (d, J = 8.78 Hz, 2 H) 8.23 (s, 1 H)B00-X00-M00(C10)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, J = 7.07Hz, 3 H) 2.83 (t, J = 7.50 Hz, 2 H) 3.01 (t, J = 7.56 Hz, 2 H) 4.35 (q,J = 7.07 Hz, 2 H) 6.02 (s, 2 H) 7.57 (ddd, J = 7.53, 4.85, 1.04 Hz, 1 H)7.68 (dt, J = 7.99, 0.95 Hz, 1 H) 8.05 (td, J = 7.74, 1.95 Hz, 1 H) 8.21(s, 1 H) 8.53 (ddd, J = 4.88, 1.83, 0.85 Hz, 1 H) B00-X00-M00(C16)-D01¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, 3 H, J = 7.07 Hz) 2.82 and 3.01(2t, 4 H, J = 7.68 Hz) 4.34 (q, 2 H, J = 7.68 Hz) 6.06 (s, 2 H)7.46-7.60 (2m, 5 H) 8.22 (s, 1 H) B00-X00-M00(C17)-D01 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.32 (t, 3 H, J = 7.20 Hz) 2.76 and 2.96 (2t, 4 H, J =7.31 Hz) 4.29 (q, 2 H, J = 7.20 Hz) 6.09 (s, 2 H) 6.64 (s, 2 H) 7.34 (m,5 H) 8.19 (s, 1 H) B00-X00-M00(C20)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32 (t, 3 H, J 7.19 Hz) 2.09 (m, 4 H) 3.85 (m, 4 H) 4.31 (q, 2 H, J7.19 Hz) 5.88 (m, 1 H) 6.67 (bs, 2 H) 8.08 (s, 1 H) 8.21 (s, 1 H).B00-X00-M00(C19)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J = 7.07Hz, 3 H) 1.93-2.16 (m, 4 H) 2.24-2.43 (m, 5 H) 2.74 (t, J = 7.62 Hz, 2H) 2.88-3.02 (m, 4 H) 4.31 (q, J = 7.07 Hz, 2 H) 5.48-5.69 (m, 1 H) 6.56(s, 2 H) 8.20 (s, 1 H) B00-X00-M00(C21)-D01 B00-X00-M00(C22)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.32 (t, J = 7.07 Hz, 3 H) 1.74-2.06 (m, 4 H)2.08 (s, 3 H) 2.73-2.78 (m, 2 H) 2.74-2.86 (m, 1 H) 2.94 (t, J = 7.62Hz, 2 H) 3.28-3.36 (m, 1 H) 3.91-4.04 (m, 1 H) 4.30 (q, J = 7.11 Hz, 2H) 4.48-4.59 (m, 1 H) 5.78-5.97 (m, 1 H) 6.61 (s, 2 H) 8.20 (s, 1 H)B00-X00-M00(C23)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J = 7.07Hz, 3 H) 2.32 (s, 6 H) 2.76 (t, J = 7.68 Hz, 2 H) 2.94 (t, J = 7.50 Hz,2 H) 3.34 (m, 2 H) 4.30 (q, J = 7.07 Hz, 2 H) 4.61 (m, 2 H) 6.55 (s, 2H) 8.19 (s, 1 H) B00-X00-M00(C24)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32 (t, J = 7.07 Hz, 3 H) 1.71 (m, 2 H) 2.32 (s, 6 H) 2.76 (t, J = 7.68Hz, 2 H) 2.94 (t, J = 7.50 Hz, 2 H) 3.34 (m, 2 H) 4.30 (q, J = 7.07 Hz,2 H) 4.61 (m, 2 H) 6.55 (s, 2 H) 8.19 (s, 1 H) B10-X00-M00(C19)-D01 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.33 (m, 3 H) 2.53-2.51 (m, 6 H) 2.97 and2.51 (2t, 4 H J 7.44 Hz) 3.13 (m, 4 H) 4.30 (m, 2 H) 6.96 (m, 2 H) 7.37(m, 2 H) 8.37 (s, 1 H) 9.14 (s, 1 H). B04-X00-M00(C21)-D01 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.34 (t, J = 7.07 Hz, 3 H) 1.89-1.96 (m, 2 H)2.00-2.15 (m, 4 H) 2.79-2.89 (m, 4 H) 2.98 (t, J = 7.87 Hz, 2 H) 3.52(s, 2 H) 4.32 (q, J = 7.15 Hz, 2 H) 5.48-5.66 (m, 1 H) 6.99-7.09 (m, 1H) 7.21-7.43 (m, 7 H) 7.59 (dd, J = 8.60, 1.04 Hz, 2 H) 8.43 (s, 1 H)9.45 (s, 1 H) B10-X00-M04(C15)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32(t, 3 H) 2.26 (m, 7 H) 2.98 (m, 6 H) 3.33 (m, 2 H) 4.30 (q, 2 H) 6.32(s, 2 H) 6.70 (d, 2 H) 7.33 (d, 2 H) 7.39 (m, 1 H) 7.47 (m, 2 H) 7.67(m, 3 H) 8.42 (m, 1 H) 9.29 (m, 1 H) B10-X00-M00(C15)-D01 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.31 (t, 3 H) 2.30 (m, 4 H) 2.52 (m, 5 H) 2.86 (m, 2H) 3.07 (m, 4 H) 4.33 (q, 2 H) 6.03 (s, 1 H) 6.88 (d, 2 H) 7.39 (m, 1 H)7.51 (m, 2 H) 7.65 (m, 5 H) 8.36 (s, 1 H) 9.42 (s, 1 H)

Example 17 Step 8. Ethyl8-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B13-X00-M03 (C01)-D01]

A solution of ethyl6-[(dimethylamino)methylene]-1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate(0.50 g, 1.6 mmol) andN-[3-chloro-4-(4-methylpiperazin-1-yl)-phenyl]-guanidine (0.48 g, 1.8mmol) in anhydrous dimethylformamide was heated to 100° C. and kept atthis temperature for 37 hours. After cooling, the mixture was dilutedwith water (50 mL) and the resulting precipitate was collected byfiltration and dried to give the title compound (0.72 g, 85% yield) as ayellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (m, 9H) 2.75 (s, 2H) 2.84 (s, 3H)3.33 (m, 8H) 4.32 (q, J 7.07 Hz, 2H) 4.37 (s, 3H) 7.20 (d, J 8.78 Hz,1H) 7.57 (dd, J 8.84, 2.50 Hz, 1H) 8.01 (d, J 2.44 Hz, 1H) 8.44 (s, 1H)9.68 (s, 1H).

By working according to this methodology, and by taking into accountthat when the guanidine derivative is available as a salt,stoichiometric amounts of potassium carbonate were employed, thefollowing compounds were prepared:

-   Ethyl    1,4,4-trimethyl-8-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B12-X00-M03(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J 7.13 Hz, 3H) 1.34 (s, 6H)2.24 (s, 3H) 2.46 (s, 4H) 2.75 (s, 2H) 2.84 (t, J 4.63 Hz, 4H) 4.32 (q,J 7 11 Hz, 2H) 4.34 (s, 3H) 7.54 (d, J 8 78 Hz, 1H) 7.93 (dd, J 8.84,2.50 Hz, 1H) 8.06 (d, J 2.44 Hz, 1H) 8.45 (s, 1H) 9.78 (s, 1H);

-   Ethyl    8-anilino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B04-X00-M03(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (m, 9H) 2.74 (s, 2H) 4.32 (q, J7.15 Hz, 2H) 4.36 (s, 3H) 6.98 (tt, J 7.36, 1.07, 1.04 Hz, 1H) 7.31 (dd,J 8.47, 7.38 Hz, 2H) 7.71 (dd, J 8.60, 0.91 Hz, 2H) 8.42 (s, 1H) 9.54(s, 1H);

-   Ethyl    8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B10-X00-M03(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.07 Hz, 3H) 1.33 (s, 6H)2.27 (s, 3H) 2.52 (m, 4H) 2.71 (s, 2H) 3.03-3.15 (m, 4H) 4.32 (q, J=7.07Hz, 2H) 4.33 (s, 3H) 6.91 (d, J=9.02 Hz, 2H) 7.53 (d, J=9.02 Hz, 2H)8.35 (s, 1H) 9.28 (s, 1H);

-   Ethyl    8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B00-X00-M03(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.31 (s, 6H)2.64 (s, 2H) 4.31 (q, J=7.07 Hz, 2H) 4.33 (s, 3H) 6.61 (s, 2H) 8.18 (s,1H).

Example 18 Ethyl8-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,5,5-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B13-X00-M02(C01)-D01]

A solution of ethyl6-(hydroxymethylene)-1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate(400 mg, 1.44 mmol) andN-[3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine (424 mg, 1.58mmol) in anhydrous dimethylformamide (5 mL) was heated at 100° C. for 3hours. After cooling, the reaction mixture was poured into brine (50 mL)and extracted with ethyl acetate (50 mL×2). The extracts were collected,dried on Na₂SO₄ and evaporated to dryness. The crude material waspurified by flash chromatography on silica gel eluted withdichloromethane/methanol 9:1 to give the pure title compound (240 mg,33% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (m, 9H) 2.27 (s, 3H) 2.52 (m, 4H)2.92 (s, 2H) 2.95 (t, J 4.63 Hz, 4H) 4.31 (q, J 7.07 Hz, 2H) 4.39 (s,3H) 7.14 (d, J 8.78 Hz, 1H) 7.52 (dd, J 8.78, 2.44 Hz, 1H) 7.98 (d, J2.44 Hz, 1H) 8.54 (s, 1H) 9.63 (s, 1H).

By working according to this methodology, and by taking into accountthat when the guanidine derivative is available as a salt,stoichiometric amounts of potassium carbonate were employed, thefollowing compounds were prepared:

-   Ethyl    1,5,5-trimethyl-8-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B12-X00-M02(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (m, 9H) 2.27 (s, 3H) 2.52 (m, 4H)2.86 (t, J 4.51 Hz, 4H) 2.93 (s, 2H) 4.32 (q, J 7.15 Hz, 2H) 4.37 (s,3H) 7.54 (d, J 8.66 Hz, 1H) 7.93 (dd, J 8.78, 2.56 Hz, 1H) 8.09 (d, J2.44 Hz, 1H) 8.56 (s, 1H) 9.81 (s, 1H);

-   Ethyl    8-anilino-1,5,5-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B04-X00-M02(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (m, 9H) 2.93 (s, 2H) 4.31 (q, J7.15 Hz, 2H) 4.38 (s, 3H) 6.98 (tt, J 7.36, 1.07, 1.04 Hz, 1H) 7.32 (dd,J 8.47, 7.50 Hz, 2H) 7.72 (dd, J 8.60, 1.04 Hz, 2H) 8.53 (s, 1H) 9.57(s, 1H);

-   Ethyl    1,5,5-trimethyl-8-{[4-(4-methylpiperazin-1-yl)-phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B10-X00-M02(C01)-D01]

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.30 (s, 6H) 1.34 (t, J=7.07 Hz, 3H)2.25 (s, 3H) 2.48 (m, 4H) 2.91 (s, 2H) 3.09 (m, 4H) 4.31 (q, J=7.19 Hz,2H) 4.35 (s, 3H) 6.92 (d, J=9.29 Hz, 2H) 7.52 (d, J=9.29 Hz, 2H) 8.46(s, 1H) 9.30 (s, 1H);

-   Ethyl    1,5,5-trimethyl-8-amino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B00-X00-M02(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (s, 6H) 1.32 (t, J=7.13 Hz, 3H)2.86 (s, 2H) 4.30 (q, J=7.07 Hz, 2H) 4.35 (s, 3H) 6.61 (s, 2H) 8.29 (s,1H).

Example 19 Ethyl8-(1-acetyl-piperidin-4-yl)amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B91-X00-M00(C01)-D01]

To a suspension of 5.187 g (19 mmol) of ethyl8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatein dry dimethylformamide (120 mL), were added 1-acetyl-4-piperidone (4.7mL, 38 mmol), CF₃COOH (10 mL, 128 mmol) and NaBH(OAc)₃ (8.862 g, 42mmol). After 18 hours, NaOH 0.33N (800 mL, 264 mmol) was added dropwiseto the mixture. The precipitate was filtered, washed with water anddried in oven to dryness to give 5.3 g (70% yield) of the titlecompound.

¹H NMR (400 MHz), DMSO-d₆) δ ppm 1.34 (t, J 7.07 Hz, 3H) 1.47 (m, 2H)1.95 (m, 2H) 2.02 (s, 3H) 2.73 (m, 1H) 2.77 (m, 2H) 3.17 (m, 1H) 3.83(m, 1H) 3.95 (m, 1H) 4.30 (q, J 0.07 Hz, 2H) 4.31 (m, 1H) 4.33 (s, 3H)7.14 (m, 1H) 8.24 (s, 1H)

By working according to the above method the following compounds wereprepared:

TABLE VIII B73-X00-M00(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t,J 7.13 Hz, 3 H) 1.54 (m, 4 H) 1.70 (m, 2 H) 1.94 (m, 2 H) 2.77 (m, 2 H)2.94 (t, J 7.74 Hz, 2 H) 4.17 (m, 1 H) 4.30 (q, J 7.07 Hz, 2 H) 4.35 (s,3 H) 7.11 (d, J 6.34 Hz, 1 H) 8.22 (s, 1 H) B89-X00-M00(C01)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.20 (t, J 7.07 Hz, 3 H) 1.32 (t, J 7.13 Hz, 3H) 1.41 (m, 2 H) 1.92 (dd, J 12.62, 2.99 Hz, 2 H) 2.89 (m, 6 H) 3.94 (m,3 H) 4.05 (q, J 7.07 Hz, 2 H) 4.30 (q, J 7.19 Hz, 2 H) 4.33 (s, 3 H)7.13 (d, J 5.85 Hz, 1 H) 8.24 (s, 1 H) B27-X00-M00(C01)-D01 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.08-1.37 (m, 5 H) 1.32 (t, J = 7.07 Hz, 3 H)1.53-1.99 (m, 5 H) 2.76 (t, J = 7.62 Hz, 2 H) 2.94 (t, J = 7.50 Hz, 2 H)3.62-3.77 (m, 1 H) 4.30 (q, J = 7.15 Hz, 2 H) 4.34 (s, 3 H) 6.98 (d, J =5.37 Hz, 1 H) 8.21 (s, 1 H) B90-X00-M00(C01)-D01 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.32 (t, J = 7.07 Hz, 3 H) 1.54 (m, 2 H) 1.89 (d, J =12.80 Hz, 2 H) 1.96 (m, 2 H) 2.18 (s, 3 H) 2.77 (m, 4 H) 2.94 (t, J =7.74 Hz, 2 H) 3.66 (m, 1 H) 4.30 (q, J = 7.19 Hz, 2 H) 4.33 (s, 3 H)7.03 (d, J = 6.46 Hz, 1 H) 8.22 (s, 1 H) B94-X00-M00(C01)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.31 (t, J = 7.2 Hz, 3 H); 1.58 (m, 2 H); 1.98(m, 2 H); 2.75 (m, 2 H); 2.92 (m, 2 H); 3.30 (m, 2 H); 3.59 (m, 2 H);3.72 (m, 1 H); 4.26 (s, 3 H); 4.29 (q, J = 7.2 Hz, 2 H); 7.13 (d, J =7.2 Hz, 1 H); 7.68 (m, 2 H); 7.75 (m, 1 H); 7.78 (m, 2 H); 8.20 (s, 1 H)B100-X00-M00(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J = 7.2Hz, 3 H); 1.45 (m, 2 H); 1.90 (m, 2 H); 2.19 (m, 3 H); 2.31 (m, 4 H);2.77 (m, 2 H); 2.87 (m, 2 H), 2.94 (m, 2 H); 3.15 (m, 4 H); 3.60 (m, 2H); 3.87 (m, 1 H); 4.30 (q, J = 7.2 Hz, 2 H); 4.33 (s, 3 H), 7.13 (bs, 1H); 8.23 (s, 1 H) B73-X00-M00(C09)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.10-1.24 (m, 4 H) 1.34 (t, J = 7.13 Hz, 3 H) 1.40-1.62 (m, 4 H) 2.83(t, J = 7.62 Hz, 2 H) 3.03 (t, J = 7.44 Hz, 2 H) 3.83 (s, 3 H) 3.85-3.87(m, 1 H) 4.34 (q, J = 7.15 Hz, 2 H) 6.94 (s, 1 H) 7.05 (d, J = 8.90 Hz,2 H) 7.46 (d, J = 9.02 Hz, 2 H) 8.18 (s, 1 H) B73-X00-M00(C10)-D01 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.67 (m, 8 H) 1.34 (t, J = 7.13 Hz, 3H) 2.85 (t, J = 7.68 Hz, 2 H) 3.03 (t, J = 7.68 Hz, 2 H) 3.28-3.44 (m, 1H) 4.35 (q, J = 7.07 Hz, 2 H) 6.93 (s, 1 H) 7.82 (d, J = 8.78 Hz, 2 H)8.04 (d, J = 8.66 Hz, 2 H) 8.22 (s, 1 H) B73-X00-M00(C08)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.05-1.54 (m, 8 H) 1.34 (t, J = 7.13 Hz, 3 H)2.85 (t, J = 7.62 Hz, 2 H) 3.03 (t, J = 7.44 Hz, 2 H) 3.25-3.42 (m, 1 H)4.30-4.41 (m, J = 7.07, 7.07, 7.07 Hz, 2 H) 6.87 (s, 1 H) 7.48 (s, 2 H)7.79 (d, J = 8.78 Hz, 2 H) 7.95 (d, J = 8.78 Hz, 2 H) 8.22 (s, 1 H)B73-X00-M00(C11)-D01 B73-X00-M00-(C19)-D01 B91-X00-M00(C19)-D01 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.32 (t, 3 H, J = 7.08) 2.04 (s, 3 H) 2.75 and2.94 (2t, 4 H, J = 7.32) 4.31 (q, 2 H, J = 7.08) 8.26 (s, 1 H)B73-X00-M00 (C20)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.35 (m, 3 H)1.50-1.63 (m, 4 H) 1.66-2.17 (m, 8 H) 2.72-2.86 (m, 1 H) 2.76-2.81 (m, 2H) 2.94 (t, J = 7.74 Hz, 2 H) 3.11-3.27 (m, 1 H) 3.86-3.97 (m, 1 H)4.12-4.23 (m, 1 H) 4.30 (q, J = 7.15 Hz, 2 H) 4.34-4.44 (m, 1 H)5.82-5.98 (m, 1 H) 7.14 (s, 1 H) 8.08 (s, 1 H) 8.24 (s, 1 H)B73-X00-M00(C22)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, 3H, J =7.07) 2.09 (s, 3H) 2.94 and 2.76 (2t, 4H, J = 7.68) 3.18 (m, 1H) 4.02(m, 1H) 4.18 (m, 1H) 4.30 (q, 2H, J = 7.07 Hz) 4.56 (m, 1H) 5.88 (m, 1H)7.13 (bs, 1H) 8.24 (s, 1H) B91-X00-M00(C22)-D01 B73-X00-M00(C023)-D01 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J = 7.07 Hz, 3 H) 1.65 (m, 6 H)1.94 (m, 2 H) 2.32 (s, 6 H) 2.73 (m, 2 H) 2.95 (t, J 7.62 Hz, 2 H) 3.34(m, 2 H) 4.17 (m, 1 H) 4.31 (q, J = 7.03 Hz, 2 H) 4.61 (m, 2 H) 8.20 (s,1 H) B73-X00-M00(C024)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J =7.07 Hz, 3 H) 1.65 (m, 6 H) 1.94 (m, 2 H) 2.29 (s, 6 H) 2.50 (m, 2 H)2.73 (m, 2 H) 2.95 (t, J 7.62 Hz, 2 H) 4.17 (m, 1 H) 4.31 (q, J = 7.03Hz, 2 H) 4.54 (m, 2 H) 8.20 (s, 1 H) B95-X00-M00(C01)-D01B91-X00-M03(C01)-D01 ¹H NMR (400 MHz), DMSO-d₆) δ ppm 1.31 (s, 6 H) 1.32(t, J = 7.07 Hz, 3 H) 1.49 (m, 2 H) 1.96 (m, 2 H) 2.02 (s, 3 H) 2.65 (s,2 H) 2.76 (m, 1 H) 3.16 (m, 1 H) 3.83 (m, 1 H) 3.95 (m, 1 H) 4.30 (m, 1H) 4.31 (q, J = 7.03 Hz, 2 H) 4.32 (s, 3 H) 7.17 (s, 1 H) 8.24 (s, 1 H)B89-X00-M03(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (t, J = 7.07Hz, 3 H) 1.33 (s, 6 H) 1.35 (t, J = 7.14 Hz, 3 H) 1.43 (m, 2 H) 1.95(dd, J = 12.43, 2.54 Hz, 2 H) 2.67 (s, 2 H) 2.98 (m, 2 H) 3.92 (m, 1 H)3.99 (m, 2 H) 4.08 (q, J = 7.00 Hz, 2 H) 4.33 (q, J = 7.10 Hz, 2 H) 4.34(s, 3 H) 7.17 (s, 1 H) 8.25 (s, 1 B73-X00-M03(C01)-D01 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.31 (s, 6 H) 1.32 (t, J = 7.13 Hz, 3 H) 1.55 (m, 4 H)1.70 (m, 2 H) 1.94 (m, 2 H) 2.64 (s, 2 H) 4.17 (m, 1 H) 4.31 (q, J =7.11 Hz, 2 H) 4.34 (s, 3 H) 7.12 (d, J = 7.19 Hz, 1 H) 8.21 (s, 1 H)B92-X00-M03(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J = 7.07Hz, 3 H) 1.31 (s, 6 H) 1.46 (m, 2 H) 1.96 (m, 2 H) 2.65 (s, 2 H) 3.18(m, 2 H) 3.62 (m, 1 H) 4.01 (m, 1 H) 4.31 (q, J = 7.03 Hz, 2 H) 4.32 (s,3 H) 4.40 (m, 1 H) 7.18 (s, 1 H) 7.34-7.49 (m, 5 H) 8.23 (s, 1 H)B93-X00-M03(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 6 H) 1.31(t, J = 7.19 Hz, 3 H) 1.59 (m, 2 H) 2.01 (m, 2 H) 2.89 (s, 3 H) 2.90 (m,2 H) 3.56 (m, 2 H) 3.87 (m, 1 H) 4.30 (q, J = 7.03 Hz, 2 H) 4.32 (s, 3H) 8.24 (s, 1 H) B94-X00-M03(C01)-D01 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.29 (s, 6 H) 1.31 (t, J = 7.19 Hz, 3 H) 1.59 (m, 2 H) 1.99 (m, 2 H)2.56 (m, 2 H) 2.63 (s, 2 H) 3.59 (m, 2 H) 3.73 (m, 1 H) 4.25 (s, 3 H)4.30 (q, J = 7.03 Hz, 2 H) 7.14 (d, J = 6.83 Hz, 1 H) 7.68 (m, 2 H) 7.73(m, 1 H) 7.77 (m, 2 H) 8.19 (s, 1 H) B91-X00-M05 ¹H NMR (400 MHz),DMSO-d₆) δ ppm 1.37 (m, 2 H) 1.89 (m, 2 H) 2.02 (s, 3 H) 2.75 (m, 1 H)2.93 (m, 2 H) 3.17 (m, 1 H) 3.64 (m, 2 H) 3.81 (m, 1 H) 4.01 (m, 1 H)4.26 (m, 1 H) 4.36 (m, 2 H) 6.54 (bs, 1 H) 7.17 (s, 1 H) 8.23 (s, 1 H)

Example 20 Ethyl8-methoxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[367-X03-M00(C01)-D01]

2.0 g (7.2 mmol) of ethyl6-[(dimethylamino)methylene]-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylatewere dissolved in 200 mL of acetonitrile and 17.4 g (70.6 mmol) ofmethylisourea sulfate and 10.0 g (72.4 mmol) of potassium carbonate wereadded. The reaction mixture was stirred at reflux for 16 hours. Thesolvent was then evaporated, the residue redissolved withdichloromethane and washed with water. The organic layer was dried overanhydrous Na₂SO₄ and concentrated. After a chromatography on a silicagel column (eluant dichloromethane) 1.7 g of product were obtained (86%yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J 7.07 Hz, 3H) 2.98 (m, 4H)3.97 (s, 3H) 4.31 (q, J 7.07 Hz, 2H) 4.34 (s, 3H) 8.54 (s, 1H).

Example 21 Ethyl8-hydroxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B00-X03-M00(C01)-D01]

1.5 g (5.2 mmol) of ethyl8-methoxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatewere dissolved in 90 mL of acetonitrile and 1.6 g (10.6 mmol) of sodiumiodide and 1.5 mL of trimethylsilylchloride were added. After a dayunder stirring and nitrogen atmosphere at room temperature the solventwas evaporated, the residue redissolved with a mixturedichloromethane/methanol 4/1 and washed with a saturated aqueoussolution of Na₂S₂O₃. The organic layer was dried over Na₂SO₄ andevaporated to dryness. The residue crystallized from methanol leading1.1 g of the title compound (78% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J 7.07 Hz, 3H) 2.84 (m, 4H)4.31 (q, J 7.07 Hz, 2H) 4.29 (s, 3H) 7.87 (s, 1H) 11.70 (s, 1H).

Example 22 Ethyl1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B66-X03-M00(C01)-D01]

0.60 g (2.19 mmol) of ethyl8-hydroxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylateand 0.31 mL (2.19 mmol) of triethylamine were dissolved in 60 mL ofdichloromethane and stirred for 5 hours at −78° C.; then, 0.72 mL (2.19mmol) of triflic anhydride were added. The reaction was stirredovernight and allowed to come to room temperature, washed with aqueousNaHCO₃, dried over Na₂SO₄ and evaporated to dryness. The residue wastriturated with diethyl ether/acetone and the product collected byfiltration giving 0.60 g (67% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J 7.13 Hz, 3H) 3.09 (s, 4H)4.28 (s, 3H) 4.32 (q, J 7.11 Hz, 2H) 8.86 (s, 1H).

Example 23 Ethyl8-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B97-X00-M00(C01)-D01]

To a solution of 1.5 g (3.7 mmol) of ethyl1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatein 150 mL of anhydrous dioxane, 756 mg (4.1 mmol) of tert-butyl3-aminopyrrolidine-1-carboxylate were added. The reaction mixture wasstirred at room temperature overnight. The solvent was then removedunder reduced pressure, the residue redissolved with dichloromethane andwashed with water. The organic layer was dried over sodium sulfate andevaporated. 1.2 g (88% yield) of the title compound was collected byfiltration after trituration with diethylether.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.38-1.44 (m,9H) 1.81-1.99 (m, 1H) 2.09-2.23 (m, 1H) 2.79 (t, J=7.68 Hz, 2H) 2.95 (t,J=7.80 Hz, 2H) 3.13-3.66 (m, 4H) 4.30 (q, J=7.07 Hz, 2H) 4.32-4.41 (m,1H) 4.34 (s, 3H) 7.40 (s, 1H) 8.27 (s, 1H)

Analogously, but employing the suitable amino derivative, the followingcompounds was prepared:

-   ethyl    8-[(1-benzylpyrrolidin-3-yl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B98-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, 3H, J 7.07 Hz) 2.21 and 1.79(2m, 2H) 2.51 and 2.69 (2m, 4H) 2.93 and 2.74 (2t, 4H, J 7.68 Hz) 4.30(m, 5H) 7.33 (m, 6H) 8.23 (s, 1H).

Example 24 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B00-X00-M00(C01)-D03]

2.5 g of ethyl8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (9.16 mmol)were dissolved in 40 mL of methanol, 40 mL of dimethylformamide and 50mL of NH₄OH 30% mixture. The mixture was maintained at 65° C. understirring for a day. The solvent was then evaporated to dryness, theresidue redissolved with dichloromethane and washed with water. Theorganic layer was dried over Na₂SO₄ and evaporated. The crude wastriturated with diethyl ether and the product collected by filtration(50% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.68 and 2.90 (2m, 4H) 4.28 (s, 3H) 6.50(bs, 2H) 7.13-7.42 (bs, 2H) 8.15 (s, 1H).

By working according to this method, the following compounds wereprepared:

TABLE IX B04-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.79 (m, 2H) 2.96 (m, 2 H) 4.31 (s, 3 H) 6.94 (m, 1 H) 7.22 (bs, 1 H) 7.28 (m, 2H) 7.68 (m, 2 H) 8.88 (s, 1 H) 9.48 (bs, 1 H). B06-X00-M00(C01)-D03 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.81 (m, 2 H) 2.97 (m, 2 H) 4.33 (s, 3 H)6.97 (m, 1 H) 7.29 (m, 1 H) 7.44 (bs, 1 H) 7.66 (m, 1 H) 7.98 (m, 1 H)8.43 (s, 1 H) 9.73 (bs, 1 H). B07-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.81 (t, J 7.68 Hz, 2 H) 2.98 (t, J 7.74 Hz, 2 H) 4.30(s, 3 H) 7.24 (s, 1 H) 7.26 (dd, J 8.66, 0.85 Hz, 1 H) 7.44 (s, 1 H)7.51 (t, J 7.93 Hz, 1 H) 7.90 (d, J 8.05 Hz, 1 H) 8.19 (s, 1 H) 8.45 (s,1 H) 9.87 (s, 1 H) B08-X00-M00(C01)-D03 B09-X00-M00(C01)-D03 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.73 (m, 2 H) 2.97 (m, 2 H) 4.31 (s, 3 H) 6.58 (m, 1H) 7.00-7.40 (3m, 4 H) 8.37 (s, 1 H) 9.32 (bs, 1 H).B10-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.64 (s, 3 H) 2.76(m, 2 H) 2.95 (m, 2 H) 4.29 (s, 3 H) 6.92 (m, 2 H) 7.23 (bs, 1 H) 7.41(bs, 1 H) 7.54 (m, 2 H) 8.32 (s, 1 H) 9.27 (bs, 1 H).B36-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.76 (m, 2 H) 2.95(m, 2 H) 4.28 (s, 3 H) 5.95 (s, 2 H) 6.84 (m, 1 H) 7.06 (m, 1 H) 7.34(m, 1 H) 7.22 (bs, 1 H) 7.42 (bs, 1 H) 8.34 (s, 1 H) 9.34 (bs, 1 H).B04-X00-M00(C02)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.77 (s, 9H) 2.72(m, 2 H) 2.96 (m, 2 H) 7.02 (m, 1 H) 7.20-7.40 (m, 3 H) 7.65 (m, 1 H)7.67 (m, 1 H) 8.40 (s, 1 H) 9.21 (bs, 1 H). B04-X00-M00(C04)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.78 (t, J 7.68 Hz, 2 H) 2.96 (t, J 7.74 Hz, 2H) 3.83 (q, J 5.69 Hz, 2 H) 4.78 (t, J 5.49 Hz, 1 H) 4.84 (t, J 5.79 Hz,2 H) 6.94 (t, J 7.38 Hz, 1 H) 7.23 (s, 1 H) 7.28 (m, 2 H) 7.43 (s, 1 H)7.67 (d, J 7.68 Hz, 2 H) 8.37 (s, 1 H) 9.42 (s, 1 H)B04-X00-M00(C07)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.98 (m, 4 H) 5.47(s, 2 H) 6.97 (t, J 7.32 Hz, 1 H) 7.31 (t, 4 H) 7.49 (s, 1 H) 7.65 (t, J7.68 Hz, 3 H) 8.41 (s, 1 H) 9.48 (s, 1 H) B04-X00-M00(C08)-D03B04-X00-M00(C09)-D03 B04-X00-M00(C10)-D03 B04-X00-M00(C05)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.86 (m, 2 H) 2.92 (m, 2 H) 5.44 (q, J 9.02, 2H) 6.90 (m, 1 H) 7.24 (m, 2 H) 7.80 (m, 3 H) 7.93 (bs, 1 H) 8.40 (s, 1H) 9.72 (bs, 1 H). B04-X00-M04(C05)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.83 (m, 2 H) 3.00 (m, 2 H) 5.75 (q; J 8.90 Hz, 2 H) 6.97 (m, 1 H) 7.28(m, 2 H) 7.40 (bs, 1 H) 7.56 (m, 2 H) 8.42 (s, 1 H) 9.56 (bs, 1 H)B04-X00-M00(C11)-D03 B04-X00-M00(C00)-D03 ¹H NMR (400 MHz, DMSO-d₆) δppm 2.86 (m, 2 H) 3.03 (m, 2 H) 6.95 (m, 1 H) 7.30 (m, 3 H) 7.51 (bs, 1H) 7.89 (m, 2 H) 8.40 (s, 1 H) 9.45 (bs, 1 H) 14.03 (bs, 1 H).B12-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.52(m, 4 H) 2.90 (m, 8 H) 4.33 (s, 3 H) 7.27 (s, 1 H) 7.47 (s, 1 H) 7.53(d, J 8.78 Hz, 1 H) 7.93 (dd, J 8.90, 2.44 Hz, 1 H) 8.08 (d, J 2.56 Hz,1 H) 8.45 (s, 1 H) 9.76 (s, 1 H) B13-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.52 (m, 4 H) 2.92 (m, 8 H) 4.35 (s, 3 H)7.14 (d, J 8.78 Hz, 1 H) 7.27 (s, 1 H) 7.47 (s, 1 H) 7.53 (dd, J = 8.78,2.44 Hz, 1 H) 7.97 (d, J = 2.56 Hz, 1 H) 8.42 (s, 1 H) 9.58 (s, 1 H)B27-X00-M00(C03)-D03 B27-X00-M04(C03)-D03 ¹H NMR (400 MHz, DMSO-d₆) δppm 0.79 (s, 3 H) 1.64 (m, 2 H) 4.85 (m, 2 H) 6.67 (m, 1 H) 7.16-7.24(m, 3 H) 7.25-7.42 (2 bs, 2 H) 9.25 (bs, 1 H). B04-X00-M00(C21)-D03 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.92 (dd, J = 11.58, 4.15 Hz, 2 H)2.01-2.10 (m, 2 H) 2.12-2.23 (m, 2 H) 2.80 (t, J = 7.56 Hz, 2 H) 2.88(d, J = 11.10 Hz, 2 H) 2.98 (t, J = 7.50 Hz, 2 H) 3.52 (s, 2 H)5.48-5.61 (m, 1 H) 6.99-7.07 (m, 1 H) 7.26 (s, 1 H) 7.27-7.39 (m, 7 H)7.43 (s, 1 H) 7.60 (dd, J = 8.54, 1.10 Hz, 2 H) 8.41 (s, 1 H) 9.43 (s, 1H) B00-X00-M00(C21)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.94 (d, J =11.95 Hz, 2 H) 2.10-2.33 (m, 4 H) 2.70 (t, J = 7.74 Hz, 2 H) 2.93 (t, J= 7.56 Hz, 4 H) 3.55 (s, 2 H) 5.41-5.69 (m, 1 H) 6.51 (s, 2 H) 7.15-7.43(m, 7 H) 8.17 (s, 1 H) B10-X00-M00(C19)-D03 ¹H NMR (400 MHz, DMSO-d₆) δppm 2.51 (m, 4 H) 2.79 (m, 4 H) 3.13 (m, 4 H) 5.46 (m, 1 H) 6.95 (m, 2H) 7.38 (m, 2 H) 7.36 and 7.26 (2s, 2 H) 8.34 (s, 1 H) 9.12 (s, 1 H).B04-X00-M04(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.83 (t, J = 7.68Hz, 2 H) 3.00 (t, J = 7.62 Hz, 2 H) 4.34 (s, 3 H) 6.92-7.03 (m, 1 H)7.26 (s, 1 H) 7.31 (dd, J = 8.41, 7.44 Hz, 2 H) 7.47 (s, 1 H) 7.72 (dd,J = 8.60, 0.91 Hz, 2 H) 8.42 (s, 1 H) 9.51 (s, 1 H) B73-X00-M00(C05)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42-1.78 (m, 6 H) 1.84-2.00 (m, 2 H)2.78 (t, J = 7.74 Hz, 2 H) 2.98 (t, J = 7.74 Hz, 2 H) 4.02-4.20 (m, 1 H)5.81 (q, J = 8.82 Hz, 2 H) 7.22 (d, J = 6.95 Hz, 1 H) 7.41 (s, 1 H) 7.45(s, 1 H) 8.25 (s, 1 H) B73-X00-M00(C04)-D03 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.41-1.77 (m, 6 H) 1.84-2.01 (m, 2 H) 2.73 (t, J = 7.74 Hz, 2 H)2.95 (t, J = 7.56 Hz, 2 H) 3.85 (t, J = 6.10 Hz, 2 H) 4.09-4.25 (m, 1 H)4.73-4.90 (m, 1 H) 4.82 (t, J = 6.16 Hz, 2 H) 7.04 (d, J = 5.98 Hz, 1 H)7.24 (s, 1 H) 7.43 (s, 1 H) 8.20 (s, 1 H) B73-X00-M00(C21)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.71 AND 2.94 (2T, 4 H, J 7.80 Hz) 3.55 (s, 2H) 4.15 (m, 1 H) 5.62 (m, 1 H) 7.25-7.36 (m, 5 H) 7.23 and 7.39 (2s, 2H) 8.20 (s, 1 H). B97-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.4 (s, 9H) 1.8-2.2 (2m, 2 H) 2.75 and 2.96 (2t, 4 H) 3.2-3.7 (m, 4 H)4.2-4.4 (m, 4 H) 7.38 (s, 1 H) 7.24 and 7.44 (2s, 2 H) 8.25 (s, 1 H).B98-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.6-2.2 (m, 2 H)2.72 (m, 4 H) 2.94 (m, 4 H) 4.27 (s, 3 H) 4.32 (m, 1 H) 7.33 (m, 6 H)7.43 (2s, 2 H) 8.21 (s, 1 H). B95-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.02 (t, J = 7.19 Hz, 3 H) 1.44-1.58 (m, 2 H) 1.87-1.94(m, 2 H) 1.95-2.03 (m, 2 H) 2.35 (q, J = 7.07 Hz, 2 H) 2.73 (t, J = 7.56Hz, 2 H) 2.89 (d, J = 11.71 Hz, 2 H) 2.94 (t, J = 7.62 Hz, 2 H)3.59-3.78 (m, 1 H) 4.30 (s, 3 H) 7.00 (d, J = 7.93 Hz, 1 H) 7.23 (s, 1H) 7.44 (s, 1 H) 8.21 (s, 1 H) B73-X00-M00(C19)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.72 and 2.94 (2t, 4 H, J 7.94 Hz) 4.20 (m, 1 H) 5.60 (m,1 H) 7.25 (s, 1 H) 1.10 and 7.35 (2s, 2 H) 8.21 (s, 1 H).B91-X00-M00(C19)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.04 (s, 3 H) 2.28(s, 3 H) 3.18 (m, 4 H) 4.30 (m, 4 H) 5.50 (m, 1 H) 7.26 (s, 1 H) 7.10and 7.36 (2s, 2 H) 8.24 (s, 1 H). B91-X00-M00(C22)-D03B73-X00-M00(C22)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (s, 3H) 2.94and 2.72 (2t, 4H, J = 7.93) 4.18 (m, 1H) 5.83 (m, 1H) 7.09 (s, 1H) 7.42and 7.23 (2s, 2H) 8.22 (s, 1H B73-X00-M00(C20)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.48-1.63 (m, 4 H) 1.66-2.15 (m, 8 H) 2.66-2.84 (m, 1 H)2.72 (t, J = 7.62 Hz, 2 H) 2.94 (t, J = 7.68 Hz, 2 H) 3.08-3.39 (m, 1 H)3.86-3.97 (m, 1 H) 4.10-4.25 (m, 1 H) 4.31-4.42 (m, 1 H) 5.77-5.95 (m, 1H) 7.08 (s, 1 H) 7.23 (s, 1 H) 7.43 (s, 1 H) 8.09 (s, 1 H) 8.22 (s, 1 H)B73-X00-M00(C16)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.64 (m, 8 H)2.80 (t, J = 7.62 Hz, 2 H) 3.03 (t, J = 7.62 Hz, 2 H) 3.27-3.33 (m, 1 H)6.77 (s, 1 H) 7.33 (s, 1 H) 7.44-7.57 (m, 5 H) 7.61 (s, 1 H) 8.17 (s, 1H) B73-X00-M00(C17)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.87 (m, 8H) 2.76 (t, J = 7.68 Hz, 2 H) 2.99 (t, J = 7.62 Hz, 2 H) 3.99 (s, 1 H)6.07 (s, 2 H) 7.06 (d, J = 7.44 Hz, 1 H) 7.13-7.35 (m, 6 H) 7.44 (s, 1H) 8.21 (s, 1 H) B73-X00-M00(C09)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.00-1.68 (m, 8 H) 2.79 (t, J = 7.62 Hz, 2 H) 3.02 (t, J = 7.62 Hz, 2 H)3.21-3.44 (m, 1 H) 3.82 (s, 3 H) 6.79 (d, J = 5.85 Hz, 1 H) 7.04 (d, J =9.02 Hz, 2 H) 7.31 (s, 1 H) 7.46 (d, J = 8.90 Hz, 2 H) 7.58 (s, 1 H)8.16 (s, 1 H) B73-X00-M00(C10)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.05-1.65 (m, 8 H) 2.82 (t, J = 7.62 Hz, 2 H) 3.03 (t, J = 7.68 Hz, 2 H)3.25-3.44 (m, 1 H) 6.90 (s, 1 H) 7.42 (s, 1 H) 7.70 (s, 1 H) 7.84 (d, J= 8.66 Hz, 2 H) 8.03 (d, J = 8.78 Hz, 2 H) 8.21 (s, 1 H)B73-X00-M00(C11)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.65 (m, 8 H)2.82 (t, J = 7.62 Hz, 2 H) 3.03 (t, J = 7.68 Hz, 2 H) 3.13-3.62 (m, 1 H)6.78 (s, 1 H) 7.37 (s, 1 H) 7.58 (ddd, J = 7.53, 4.85, 1.04 Hz, 1 H)7.65 (s, 1 H) 7.68 (dt, J = 7.93, 0.91 Hz, 1 H) 8.04-8.10 (m, 1 H) 8.18(s, 1 H) 8.57 (ddd, J = 4.85, 1.86, 0.85 Hz, 1 H) B73-X00-M00(C08)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.55 (m, 8 H) 2.82 (t, J = 7.62 Hz,2 H) 3.03 (t, J = 7.56 Hz, 2 H) 3.26-3.42 (m, 1 H) 6.82 (s, 1 H) 7.41(s, 1 H) 7.44 (s, 2 H) 7.64 (s, 1 H) 7.80 (d, J = 8.66 Hz, 2 H) 7.93 (d,J = 8.78 Hz, 2 H) 8.21 (s, 1 H)

Example 251-methyl-8-[(phenylacetyl)amino]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B05-X01-M00(C01)-D03]

0.40 g (1.47 mmol) of8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide weresuspended in 20 mL of tetrahydrofuran and 5 mL of pyridine and 0.42 mL(3.22 mmol) of phenylacetylchloride were added. The reaction mixture wasstirred at room temperature for 16 hours. The solvent was evaporated,the residue redissolved with dichloromethane, washed with aqueous NaHCO₃and then with water. After drying over anhydrous Na₂SO₄ the solvent wasremoved under reduced pressure and the crude purified by chromatographyon a silica gel column (eluant cyclohexane/acetone) giving 0.35 mg ofthe title compound (60% yield).

¹H NMR (400 MHz), DMSO-d₆) δ ppm 2.62-3.02 (2m, 4H) 3.76 (m, 2H) 4.3 (s,3H) 7.00-7.50 (m, 7H) 8.50 (s, 1H) 10.80 (bs, 1H).

By working according to this method, the following compound wasprepared:

-   8-(benzoylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B04-X01-M00(C01)-D03]

¹H NMR (400 MHz), DMSO-d₆) δ ppm 2.87-3.04 (2m, 4H) 4.33 (s, 3H)7.20-7.46 (bs, 2H) 7.47-7.53 (m, 3H) 7.90-8.00 (m, 2H) 8.60 (s, 1H)10.97 (m, 1H).

Example 26 Ethyl8-[(aminocarbonyl)amino]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B00-X02-M00(C01)-D01]

1.00 g (3.7 mmol) of ethyl8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate weredissolved in 50 mL of pyridine and 1 mL (8.0 mmol) oftrichloroacetylisocyanate were added. The mixture was stirred overnightat room temperature. The solvent was then evaporated under reducedpressure and the residue was treated with 50 mL of methanol. After 2hours under stirring the solvent was removed, the residue redissolvedwith dichloromethane and washed with a diluted solution of ammoniumhydrate. After drying over anhydrous Na₂SO₄ the organic layer wasevaporated to dryness and the residue purified by chromatography on asilica gel column (eluant: dichloromethane/acetone 4/1) leading 0.40 g(34% yield) of the title compound.

¹H NMR (400 MHz), DMSO-d₆) δ ppm 1.28 (t, J 7.07 Hz, 3H) 2.8-3.0 (2m,4H) 4.19-4.34 (1s and 1q, J 7.07 Hz, 3H) 7.04 (bs, 2H) 8.44 (bs, 1H)9.91 (bs, 1H).

Example 27 Ethyl8-{[(ethylamino)carbonyl]amino}-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B03-X02-M00(C01)-D01]

To a suspension of 18 mg (0.44 mmol) of sodium hydride 60% in mineraloil (0.37 mmol) in dry dimethylformamide, a solution of 100 mg of ethyl8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (0.37 mmol)in 5 mL of the same solvent was added dropwise at 0° C. under stirring.After 5 minutes, 0.070 mL (0.88 mmol) of ethylisocyanate were added tothe mixture and the reaction allowed to come to room temperature. After8 hours the solvent was evaporated under reduced pressure, the residueredissolved with dichloromethane and washed with water. After dryingover Na₂SO₄ the solvent was removed and the product purified bychromatography on a silica gel column (eluant dichloromethane/acetone)leading 64 mg (50% yield) of the title compound.

¹H NMR (400 MHz), DMSO-d₆) δ ppm 1.10 (t, J 7.20 Hz, 3H) 1.29 (t, J 7.07Hz, 3H) 2.76-3.04 (2m, 4H) 3.12 (m, 2H) 4.21 (q, J 7.07 Hz, 2H) 4.32 (s,3H) 8.45 (m, 1H) 8.71 (t, 1H) 9.70 (bs, 1H).

Example 288-[(aminocarbonyl)amino]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B00-X02-M00(C01)-D03]

A suspension of 0.20 g (0.63 mmol) of ethyl8-[(aminocarbonyl)amino]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatein 15 mL of a mixture to methanol/dimethylformamide/ammonium hydroxide30% 1/1/1 was stirred in a close bottle at 65° C. for 48 hours. Thesolvent was then evaporated under reduced pressure, the residueredissolved with a mixture dichloromethane/methanol 9/1 and washed withwater. The organic layer was dried over anhydrous Na₂SO₄ and evaporatedto dryness. The product was purified by chromatography on a silica gelcolumn (eluant dichloromethane/acetone/methanol) giving 0.09 g (50%yield) of the title compound.

¹H NMR (400 MHz), DMSO-d₆), δ ppm 2.91-3.09 (m, 4H) 3.81 (s, 3H) 6.47(m, 3H) 7.83 (bs, 2H) 8.58 (m, 1H).

By working according to the above method, the following compound wasprepared:

-   8-{[(ethylamino)carbonyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B03-X02-M00(C01)-D03]

¹H NMR (400 MHz), DMSO-d₆), δ ppm 1.10 (t, J 7.19 Hz, 3H) 2.82 (t, J7.62 Hz, 2H) 2.97 (t, J 7.74 Hz, 2H) 3.23 (m, 2H) 4.28 (s, 3H) 7.24 (s,1H) 7.45 (s, 1H) 8.42 (s, 1H) 8.75 (t, J 5.61 Hz, 1H) 9.67 (s, 1H).

Example 29 Ethyl8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

To a well stirred, warm suspension of ethyl8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(8.8 g, 0.032 mol) in dimethoxyethane (1.2 L) maintained in an inertatmosphere of argon, cesium iodide (9.13 g, 0.035 mol), bisublimatediodine (4.45 g, 0.018 mol), copper iodide (2.01 g, 0.01 mol) andisopentyl nitrite (7.00 mL, 6.14 g, 0.052 mol) were added in sequence.The reaction mixture was stirred vigorously at 65-70° C. for 18 hours.After cooling in a ice-water bath, the solid was filtered off and thefiltrate was diluted with dichloromethane (2.0 L), washed with 30%ammonium hydroxide (150 mL), sodium thiosulphate (300 mL), brine anddried over anhydrous Na₂SO₄. Concentrating to a volume of about 100 mLof dimethoxyethane, the crude ethyl8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylateprecipitated; it was then filtered and washed with dimethoxyethane.

Flash chromatography on silica gel (eluant: dichloromethane/methanol98:2) yielded 5.69 g of the title compound. (46% yield)

¹H NMR (400 MHz), DMSO-d₆), δ ppm 1.28 (t, J 7.07 Hz, 3H) 2.81-3.07 (2t,J 8.90 Hz, 4H) 4.24 (s, 3H) 4.27 (q, J 7.07 Hz, 2H) 8.5 (bs, 1H).

By working according to this method, the following compounds wereprepared:

-   ethyl    8-iodo-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 1.3 (s, 6H) 2.8(s, 2H) 4.3 (s, 3H) 4.3 (q, J 7.1 Hz, 2H) 8.5 (s, 1H);

-   ethyl    8-iodo-1,5,5-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J=7.19 Hz, 3H) 1.32 (s, 6H)2.96 (s, 2H) 4.31 (q, J=7.07 Hz, 2H) 4.28 (s, 3H) 8.58 (s, 1H);

-   ethyl    1-(3,3-dimethylbutyl)-8-iodo-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   ethyl    2-(3,3-dimethylbutyl)-8-iodo-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate.

Example 30 Ethyl8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B73-X00-M00(C01)-D01]

Ethyl8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(0.5 g, 1.3 mmol) and cyclopentylamine (0.65 mL, 6.5 mmol) were heatedat 100° C. under nitrogen for 3 hours. The mixture was concentratedunder reduced pressure and the residue was purified by chromatography ona silica gel column (eluant: ethyl acetate/cyclohexane 70/30) to give0.24 g of8-(cyclopentylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(54% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, J 7.13 Hz, 3H) 1.54 (m, 4H)1.70 (m, 2H) 1.94 (m, 2H) 2.77 (m, 2H) 2.94 (t, J 7.74 Hz, 2H) 4.17 (m,1H) 4.30 (q, J 7.07 Hz, 2H) 4.35 (s, 3H) 7.11 (d, J 6.34 Hz, 1H) 8.22(s, 1H)

By working according to this method, the following compounds wereprepared:

-   8-{[1-(ethoxycarbonyl)piperidin-4-yl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B89-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J 7.07 Hz, 3H) 1.32 (t, J 7.13Hz, 3H) 1.41 (m, 2H) 1.92 (dd, J 12.62, 2.99 Hz, 2H) 2.89 (m, 6H) 3.94(m, 3H) 4.05 (q, J 7.07 Hz, 2H) 4.30 (q, J 7.19 Hz, 2H) 4.33 (s, 3H)7.13 (d, J 5.85 Hz, 1H) 8.24 (s, 1H);

-   B27-X00-M00(C03)-D01-   B27-X00-M04(C03)-D01

Example 31 Potassium8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B73-X00-M00(C01)-D02]

Ethyl8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(230 mg, 0.67 mmol) was suspended in anhydrous ethanol (5 mL) andtreated with a 1.5 M solution of potassium hydroxide in ethanol (1.33mL, 3 eq.) at reflux temperature for 1.5 hours. After cooling in icebath, the resulting precipitate was collected by filtration to give thetitle compound (193 mg, 82% yield) as a crystalline solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61 (m, 6H) 1.94 (m, 2H) 2.67 (m, 2H)2.90 (m, 2H) 4.16 (m, 1H) 4.21 (s, 3H) 6.90 (d, J 6.83 Hz, 1H) 8.12 (s,1H)

By working according to the above method the following compounds wereprepared:

TABLE X B89-X00-M00(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J7.07 Hz, 3 H) 1.41 (m, 2 H) 1.92 (dd, J 12.62, 2.99 Hz, 2 H) 2.66 (m, 4H) 2.91 (m, 2 H) 3.94 (m, 3 H) 4.04 (q, J 7.07 Hz, 2 H) 4.18 (s, 3 H)7.13 (d, 1 H, J 5.85 Hz, 2 H) 8.24 (s, 1 H). B04-X00-M00(C01)-D02 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.78-2.98 (m, 1 H) 6.91-6.97 (m, 1 H) 7.25-7.30(m, 1 H) 7.66-7.71 (m, 1 H) B04-X00-M04(C01)-D02 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.74 (t, J = 7.62 Hz, 2 H) 2.95 (t, J = 7.68 Hz, 2 H)4.23 (s, 3 H) 6.95 (tt, J = 7.35, 1.13 Hz, 1 H) 7.30 (dd, J = 8.60, 7.38Hz, 2 H) 7.73 (dd, J = 8.72, 1.04 Hz, 2 H) 8.32 (s, 1 H) 9.39 (s, 1 H)B91-X00-M00(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (m, 2 H) 1.92(m, 2 H) 2.02 (s, 3 H) 2.67 (m, 1 H) 2.75 (m, 1 H) 2.90 (m, 2 H) 3.16(m, 1 H) 3.82 (m, 1 H) 3.94 (m, 1 H) 4.19 (s, 3 H) 4.28 (m, 1 H) 6.94(m, 1 H) 8.14 (s, 1 H) B94-X00-M00(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.57 (m, 2 H) 1.99 (m, 2 H) 2.55 (m, 2 H) 2.63 (m, 2 H) 2.88 (m, 2H) 3.58 (m, 2 H) 3.70 (m, 1 H) 4.11 (s, 3 H) 6.92 (d, J = 6.95 Hz, 1 H)7.68 (t, J = 7.32 Hz, 2 H) 7.72-7.76 (m, 1 H) 7.76-7.80 (m, 2 H) 8.09(s, 1 H) B94-X00-M03(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 6H) 1.59 (m, 2 H) 1.99 (m, 2 H) 2.56 (m, 2 H) 3.58 (m, 2 H) 3.70 (m, 1 H)4.08 (s, 3 H) 6.93 (s, 1 H) 7.68 (m, 2 H) 7.77 (m, 3 H) 8.08 (m, 1 H)8.18 (s, 1 H) B93-X00-M03(C01)-D02 B73-X00-M00(C04)-D02 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46-1.99 (m, 8 H) 2.75 (t, J = 7.68 Hz, 2 H) 2.93 (t, J= 7.50 Hz, 2 H) 3.83 (t, 2 H) 4.10-4.22 (m, 1 H) 4.77-4.87 (m, 3 H) 7.04(d, J = 5.97 Hz, 1 H) 8.21 (s, 1 H) 12.61 (s, 1 H) B90-X00-M00(C01)-D02B00-X00-M00(C21)-D02 B04-X00-M00(C21)-D02 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.81-1.90 (m, 2 H) 2.00-2.20 (m, 4 H) 2.72 (t, J = 7.68 Hz, 2 H)2.88 (d, J = 10.00 Hz, 2 H) 2.94 (t, J = 7.50 Hz, 2 H) 3.53 (s, 2 H)5.40-5.54 (m, 1 H) 6.96-7.04 (m, 1 H) 7.21-7.39 (m, 5 H) 7.26-7.31 (m, 2H) 7.62 (dd, J = 8.54, 0.98 Hz, 2 H) 8.32 (s, 1 H) 9.31 (s, 1 H)B10-X00-M00(C19)-D02

Example 328-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B73-X00-M00(C01)-D03]

A suspension of potassium8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(180 mg, 0.51 mmol) in anhydrous dimethylformamide (3.0 mL) andanhydrous tetrahydrofuran (3.0 mL) was treated withN-ethyl-N,N-diisopropylamine (0.175 mL, 2 eq.) andN-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (195 mg, 2eq). The mixture was then cooled to 0° C. and treated with ammonium1H-1,2,3-benzotriazol-1-ate (137 mg, 2 eq). After 5 minutes the reactionwas warmed to room temperature and kept at this temperature overnight.The reaction was diluted with water and the resulting precipitate wascollected by filtration to afford the title compound (143 mg, 90%yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65 (m, 6H) 1.94 (m, 2H) 2.73 (m, 2H)2.95 (t, J 7.62 Hz, 2H) 4.17 (m, 1H) 4.32 (s, 3H) 7.08 (d, J 6.83 Hz,1H) 7.23 (s, 1H) 7.43 (s, 1H) 8.20 (s, 1H)

By working according to the above method the following compounds wereprepared:

TABLE XI B89-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J7.07 Hz, 3 H) 1.41 (m, 2 H) 1.92 (dd, J 12.62, 2.99, 2 H) 2.74 (m, 2 H)2.91 (m, 2 H) 2.95 (m, 4 H) 3.94 (m, 3 H) 4.04 (q, J 7.07 Hz, 2 H) 4.30(s, 3 H) 7.09 (bs, 1 H) 7.23 (s, 1 H) 7.44 (s, 1 H) 8.22 (s, 1 H).B91-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (m, 2 H) 1.92(m, 2 H) 2.02 (s, 3 H), 2.74 (m, 2 H) 2.76 (m, 1 H) 2.95 (m, 2 H) 3.16(m, 1 H) 3.81 (m, 1 H) 3.94 (m, 1 H) 4.27 (m, 1 H) 4.31 (s, 3 H) 7.11(d, J 6.83 Hz, 1 H) 7.23 (s, 1 H) 7.44 (s, 1 H) 8.23 (s, 1 H)B100-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.57 (m, 2dihydrochloride H) 1.95 (d, J = 12.19 Hz, 2 H) 2.74-2.83 (m, 5 H)2.89-3.53 (m, 10 H) 3.65 (dd, J = 12.50, 7.87 Hz, 4 H) 3.96 (t, J =10.61 Hz, 1 H) 4.30 (s, 3 H) 7.29 (s, 1 H) 7.47 (s, 1 H) 7.64 (s, 1 H)8.26 (s, 1 H) 10.39 (s, 1 H) B93-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSOd₆) δ ppm 1.60 (m, 2 H) 2.01 (m, 2 H) 2.74 (m, 2 H) 2.89 (m, 7H,)3.55 (m, 2 H.) 3.86 (m, 1 H) 4.31 (s, 3 H) 7.15 (bd, 1 H) 7.24 (s, 1 H)7.44 (s, 1 H) 8.24 (s, 1 H) B92-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.52 (s, 2 H) hydrochloride 1.99 (s, 2 H) 2.78 (t, J =7.56 Hz, 2 H) 2.98 (t, J = 7.62 Hz, 2 H) 3.01-3.76 (m, 3 H) 4.05 (m, 1H) 4.30 (s, 3 H) 4.41 (m, 1 H) 7.27 (s, 1 H) 7.40 (m, 2 H) 7.47 (m, 4 H)7.60 (s, 1 H) 8.25 (s, 1 H) B95-X00-M00(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.02 (t, J = 7.19 Hz, 3 H) 1.52 (m, 2 H) 1.90 (m, 2 H)1.98 (m, 2 H) 2.35 (q, J = 7.07 Hz, 2 H) 2.73 (t, J = 7.56 Hz, 2 H) 2.89(d, J = 11.71 Hz, 2 H) 2.94 (t, J = 7.62 Hz, 2 H) 3.66 (m, 1 H) 4.30 (s,3 H) 7.00 (d, J = 7.93 Hz, 1 H) 7.23 (s, 1 H) 7.44 (s, 1 H) 8.21 (s, 1H) B73-X00-M00(C00)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65 (m, 6 H)1.94 (m, 2 H) 2.73 (m, 2 H) 2.95 (t, J 7.62 Hz, 2 H) 4.17 (m, 1 H) 7.08(d, J 6.83 Hz, 1 H) 7.23 (s, 1 H) 7.43 (s, 1 H) 8.20 (s, 1 H)B91-X00-M00(C00)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (m, 1 H); 1.46(m, 1 H); 1.90 (m, 1 H); 1.96 (m, 1 H); 2.02 (s, 3 H); 2.74 (d, J = 5Hz, 3 H); 2.74 (m, 2 H); 2.75 (m, 1 H); 2.95 (m, 2 H); 3.16 (m, 1 H);3.82 (m, 1 H); 3.95 (m, 1 H); 4.29 (m, 1 H); 4.31 (s, 3 H); 7.11 (bs, 1H); 8.05 (q, J = 4.5 Hz, 1 H); 8.23 (s, 1 H) B94-X00-M00(C01)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.53-1.68 (m, 2 H) 1.92-2.05 (m, 2 H) 2.52-2.62(m, 2 H) 2.71 (t, J = 7.62 Hz, 2 H) 2.89-2.98 (m, 2 H) 3.53-3.63 (m, 2H) 3.65-3.79 (m, 1 H) 4.24 (s, 3 H) 7.10 (d, J = 7.32 Hz, 1 H) 7.23 (s,1 H) 7.41 (s, 1 H) 7.65-7.70 (m, 2 H) 7.72-7.78 (m, 1 H) 7.76-7.80 (m, 2H) 8.19 (s, 1 H) B73-X00-M00(C023)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.65 (m, 6 H) 1.94 (m, 2 H) 2.32 (s, 6 H) 2.73 (m, 2 H) 2.95 (t, J 7.62Hz, 2 H) 3.34 (m, 2 H) 4.17 (m, 1 H) 4.61 (m, 2 H) 7.08 (d, J 6.83 Hz, 1H) 7.23 (s, 1 H) 7.43 (s, 1 H) 8.20 (s, 1 H) B73-X00-M00(C024)-D03 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.65 (m, 6 H) 1.94 (m, 2 H) 2.29 (s, 6 H)2.50 (m, 2 H) 2.73 (m, 2 H) 2.95 (t, J 7.62 Hz, 2 H) 4.17 (m, 1 H) 4.54(m, 2 H) 7.08 (d, J 6.83 Hz, 1 H) 7.23 (s, 1 H) 7.43 (s, 1 H) 8.20 (s, 1H) B79-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.82 (m, 2H) 2.05-2.16 (m, 2 H) 2.75 (d, J = 4.76 Hz, 3 H) 2.75-2.80 (m, 2 H) 2.97(t, J = 7.68 Hz, 2 H) 3.01-3.09 (m, 2 H) 3.27-3.49 (m, 2 H) 3.93-4.10(m, 1 H) 4.31 (s, 3 H) 7.59 (s, 1 H) 8.07 (q, J = 4.47 Hz, 1 H) 8.26 (s,1 H) 8.44-8.63 (m, 1 H) 8.69-8.90 (m, 1 H) B90-X00-M00(C01)-D04 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.48-1.62 (m, 2 H) 1.90 (d, J = 13.05 Hz, 2 H)2.00-2.08 (m, 2 H) 2.21 (s, 3 H) 2.70-2.76 (m, 2 H) 2.74 (d, J = 4.76Hz, 3 H) 2.78-2.84 (m, 2 H) 2.95 (t, J = 7.56 Hz, 2 H) 3.62-3.75 (m, 1H) 4.31 (s, 3 H) 7.01 (d, J = 7.68 Hz, 1 H) 8.06 (q, J = 4.59 Hz, 1 H)8.21 (s, 1 H) B90-X00-M00(C01)-D27 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.68-2.82 (m, 4 H) 2.73 and 2.95 (2t, 4 H J 7.44 Hz) 3.67 (m, 1 H) 4.30(s, 3 H) 7.01 (bs, 1 H) 8.11 (d, 1 H, J 4.51 Hz) 8.21 (s, 1 H)B89-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J = 7.07Hz, 3 H) 1.41 (m, 2 H) 1.92 (dd, J = 12.68, 2.68 Hz, 2 H) 2.70-2.79 (m,5 H) 2.95 (t, J = 7.68 Hz, 4 H) 3.84-3.99 (m, 3 H) 4.05 (q, J = 7.07 Hz,2 H) 4.30 (s, 3 H) 7.09 (d, J = 5.98 Hz, 1 H) 8.06 (q, J = 4.39 Hz, 1 H)8.22 (s, 1 H) B91-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40(m, 2 H) 1.94 (m, 2 H) 2.02 (s, 3 H), 2.74 (m, 5 H) 2.96 (m, 2 H) 3.16(m, 1 H) 3.83 (m, 1 H) 3.94 (m, 1 H) 4.27 (m, 1 H) 4.31 (s, 3 H) 7.11(d, J 6.83 Hz, 1 H) 7.23 (s, 1 H) 7.44 (s, 1 H) 8.23 (s, 1 H)B73-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (m, 4 H)hydrochloride 1.73 (m, 2 H) 1.97 (m, 2 H) 2.75 (d, J = 4.76 Hz, 3 H)2.79 (t, J = 7.62 Hz, 2 H) 2.99 (t, J = 7.68 Hz, 2 H) 4.21 (s, 1 H) 4.32(s, 3 H) 7.68-7.92 (m, 1 H) 8.12 (q, J = 4.39 Hz, 1 H) 8.24 (s, 1 H)B100-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43-1.51 (m, 2 H)1.91 (dd, J = 12.68, 3.17 Hz, 2 H) 2.21 (s, 3 H) 2.33 (s, 4 H) 2.71-2.76(m, 2 H) 2.75 (d, J = 4.76 Hz, 3 H) 2.82-2.91 (m, 2 H) 2.95 (t, J = 7.62Hz, 2 H) 3.12-3.18 (m, 4 H) 3.60 (dt, J = 13.32, 3.34 Hz, 2 H) 3.80-3.95(m, 1 H) 4.30 (s, 3 H) 7.09 (s, 1 H) 8.06 (q, J = 4.63 Hz, 1 H) 8.22 (s,1 H) B92-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (s, 2 H)hydrochloride 1.99 (s, 2 H) 2.75 (d, J = 4.76 Hz, 3 H) 2.78 (m, 2 H)2.98 (t, J = 7.68 Hz, 2 H) 3.06-3.79 (m, 3 H) 4.05 (m, 1 H) 4.30 (s, 3H) 4.41 (m, 1 H) 7.37-7.43 (m, 2 H) 7.45-7.49 (m, 3 H) 7.60 (s, 1 H)8.10 (q, J = 4.63 Hz, 1 H) 8.25 (s, 1 H) B93-X00-M00(C01)-D04 ¹H NMR(400 MHz, DMSOd₆) δ ppm 1.60 (m, 2 H) 2.01 (m, 2 H) 2.74 (m, 5 H) 2.89(m, 3 H,) 2.95 (m, 4 H) 3.56 (m, 2 H.) 3.86 (m, 1 H) 4.31 (s, 3 H) 7.15(bd, 1 H) 8.05 (m, 1 H) 8.24 (s, 1 H) B96-X00-M00(C01)-D04 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.34-1.46 (m, 2 H) 1.42 (s, 9 H) 1.84-1.94 (m, 2 H)2.71-2.77 (m, 2 H) 2.75 (d, J = 4.76 Hz, 3 H) 2.93 (m, 4 H) 3.94 (m, 3H) 4.30 (s, 3 H) 7.09 (d, J = 4.15 Hz, 1 H) 8.07 (m, 1 H) 8.22 (s, 1 H)B94-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (m, 2 H) 1.98(m, 2 H) 2.53-2.61 (m, 2 H) 2.67-2.77 (m, 2 H) 2.74 (d, J = 4.76 Hz, 3H) 2.93 (m, 2 H) 3.58 (d, J = 13.90 Hz, 2 H) 3.72 (m, 1 H) 4.24 (s, 3 H)7.10 (d, J = 7.07 Hz, 1 H) 7.64-7.71 (m, 2 H) 7.72-7.77 (m, 1 H)7.76-7.80 (m, 2 H) 8.04 (q, J = 4.59 Hz, 1 H) 8.19 (s, 1 H)B73-X00-M00(C01)-D26 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (m, 4 H)dihydrochloride 1.72 (m, 2 H) 1.97 (m, 2 H) 2.79 (m, 2 H) 2.86 (m, 11 H)3.01 (m, 2 H) 3.81 (s, 1 H) 4.03 (s, 1 H) 4.21 (m, 1 H) 4.33 (m, 3 H)7.70 (m, 1 H) 8.25 (s, 1 H) B73-X00-M00(C01)-D10 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.58 (m, 4 H) dihydrochloride 1.72 (m, 2 H) 1.96 (m, 2 H)2.79 (m, 2 H) 2.82 (d, J = 2.2 Hz, 3 H) 2.87 (m, 2 H) 3.0-3.7 (m, 6 H)4.21 (m, 1 H) 4.32 (s, 3 H) 4.60 (m, 1 H) 4.80 (m, 1 H) 7.70 (m, 1 H)8.26 (s, 1 H) B73-X00-M00(C01)-D25 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55(m, 4 H) 1.71 (m, 2 H) 1.94 (m, 2 H) 2.76 (m, 2 H) 2.94 (m, 2 H) 4.17(m, 1 H) 4.22 (d, J = 5.68 Hz, 2 H) 4.36 (s, 3 H) 7.10 (bd, 1 H) 8.22(s, 1 H) 8.35 (t, J = 5.68 Hz, 1 H) B73-X00-M00(C01)-D30 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.55 (m, 4 H) 1.71 (m, 2 H) 1.93 (m, 2 H) 2.74 (m, 2H) 2.96 (m, 2 H) 3.81 (d, J = 5.68 Hz, 2 H) 4.17 (m, 1 H) 4.35 (s, 3 H)7.07 (m, 2 H) 7.38 (bs, 1 H) 8.015 (t, J = 5.68 Hz, 1 H)8.21 (s, 1 H)B73-X00-M00(C01)-D05 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.61 (m, 4 H)1.64-1.78 (m, 2 H) 1.87-2.01 (m, 2 H) 2.67-2.89 (m, 4 H) 3.35 (s, 3 H)4.11-4.23 (m, 1 H) 4.31 (s, 3 H) 7.06 (d, J = 6.58 Hz, 1 H) 8.20 (s, 1H) 9.88 (s, 1 H) B73-X00-M00(C01)-D72 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.55 (m, 4 H) 1.71 (m, 2 H) 1.92 (m, 2 H) 2.23 (s, 6 H) 2.52 (m, 2 H)2.71 (m, 2 H) 2.91 (m, 4 H) 4.17 (m, 1 H) 4.37 (s, 3 H) 5.09 (m, 1 H)7.07 (d, J 6.83 Hz, 1 H) 7.24 (m, 1 H) 7.33 (m, 2 H) 7.42 (m, 2 H) 8.20(s, 1 H) 8.28 (m, 1 H) B73-X00-M00(C01)-D163 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.08 (m, 3 H) 1.65 (m, 6 H) 1.94 (m, 2 H) 2.17 (s, 6 H) 2.45 (m, 2H) 2.73 (m, 2 H) 2.95 (m, 2 H) 4.04 (m, 1 H) 4.17 (m, 1 H) 4.32 (s, 3 H)7.08 (d, J 6.83 Hz, 1 H) 7.91 (d, 1 H) 8.20 (s, 1 H)B94-X00-M00(C01)-D72 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61 (m, 2 H) 1.97(m, 2 H) 2.23 (s, 6 H) 2.52 (m, 2 H) 2.55 (m, 2 H) 2.70 (m, 2 H) 2.90(m, 4 H) 3.56 (m, 2 H) 3.72 (m, 1 H) 4.28 (s, 3 H) 5.10 (m, 1 H) 7.11(d, J 6.83 Hz, 1 H) 7.24 (m, 1 H) 7.33 (m, 2 H) 7.40 (m, 2 H) 7.68 (m, 2H) 7.77 (m, 3 H) 8.18 (s, 1 H) 8.27 (m, 1 H) B94-X00-M00(C01)-D163 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.14 (m, 3 H) 1.61 (m, 2 H) 2.00 (m, 2 H)2.19 (s, 6 H) 2.52 (m, 2 H) 2.55 (m, 2 H) 2.72 (m, 2 H) 2.94 (m, 2 H)3.57 (m, 2 H) 3.73 (m, 1 H) 4.10 (m, 1 H) 4.25 (s, 3 H) 7.09 (m, 1 H)7.68 (m, 2 H) 7.77 (m, 3 H) 8.19 (s, 1 H) B91-X00-M03(C01)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.32 (s, 6 H) 1.43 (m, 2 H) 1.94 (m, 2 H) 2.02(s, 3 H) 2.62 (s, 2 H) 2.76 (m, 1 H) 3.16 (m, 1 H) 3.83 (m, 1 H) 3.94(m, 1 H) 4.28 (m, 1 H) 4.29 (s, 3 H) 7.12 (d, J = 4.15 Hz, 1 H) 7.27 (s,1 H) 7.53 (s, 1 H) 8.21 (s, 1 H) B89-X00-M03(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.20 (t, J = 7.07 Hz, hydrochloride 3 H) 1.34 (s, 6 H)1.38-1.49 (m, 2 H) 1.89-1.99 (m, 2 H) 2.65 (s, 2 H) 2.90-3.04 (m, 2 H)3.90-4.00 (m, 3 H) 4.06 (q, J = 7.07 Hz, 2 H) 4.29 (s, 3 H) 7.31 (s, 1H) 7.57 (s, 1 H) 8.24 (s, 1 H) 8.41 (s, 2 H) B73-X00-M03(C01)-D03 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.35 (s, 6 H) hydrochloride 1.51-1.77 (m, 6 H)1.85-2.04 (m, 2 H) 2.67 (s, 2 H) 4.14-4.25 (m, 1 H) 4.31 (s, 3 H) 7.34(s, 1 H) 7.60 (s, 1 H) 7.86 (s, 1 H) 8.23 (s, 1 H) B92-X00-M03(C01)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (s, 6 H) 1.50 (m, 2 H) 1.99 (m, 2H) 2.62 (s, 2 H) 3.10 (m, 2 H) 3.62 (m, 1 H) 4.01 (m, 1 H) 4.29 (s, 3 H)4.40 (m, 1 H) 7.15 (s, 1 H) 7.27 (s, 1 H) 7.38 (m, 2 H) 7.47 (m, 3 H)7.53 (s, 1 H) 8.22 (s, 1 H) B94-X00-M03(C01)-D03 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.29 (s, 6 H) 1.60 (m, 2 H) 1.99 (m, 2 H) 2.52 (s, 2 H)2.59 (m, 2 H) 2.75 (d, J = 4.51 Hz, 3 H) 3.57 (m, 2 H) 3.71 (m, 1 H)4.22 (s, 3 H) 7.11 (s, 1 H) 7.68 (m, 2 H) 7.77 (m, 3 H) 8.11 (m, 1 H)8.18 (s, 1 H) B93-X00-M03(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32(s, 6 H) 1.60 (m, 2 H) 2.02 (m, 2 H) 2.62 (s, 2 H) 2.89 (m, 5 H) 3.55(m, 2 H) 3.85 (m, 1 H) 4.30 (s, 3 H) 7.15 (bd, 1 H) 7.27 (s, 1 H) 7.53(s, 1 H) 8.22 (s, 1 H) B91-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.32 (s, 6 H) 1.34-1.52 (m, 2 H) 1.87-2.00 (m, 2 H) 2.02 (s, 3 H)2.62 (s, 2 H) 2.71-2.84 (m, 1 H) 2.76 (d, J = 4.76 Hz, 3 H) 3.10-3.22(m, 1 H) 3.83 (d, J = 12.93 Hz, 1 H) 3.89-4.02 (m, 1 H) 4.23-4.35 (m, 1H) 4.30 (s, 3 H) 7.13 (d, J = 4.88 Hz, 1 H) 8.13 (q, J = 4.72 Hz, 1 H)8.22 (s, 1 H) B73-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34(s, 6 H) hydrochloride 1.50-1.65 (m, 4 H) 1.67-1.78 (m, 2 H) 1.88-2.08(m, 2 H) 2.67 (s, 2 H) 2.76 (d, J = 4.63 Hz, 3 H) 4.09-4.24 (m, 1 H)4.31 (s, 3 H) 7.84 (s, 1 H) 8.20 (q, J = 4.51 Hz, 1 H) 8.23 (s, 1 H)B92-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (s, 6 H) 1.50(m, 2 H) 1.99 (m, 2 H) 2.62 (s, 2 H) 2.75 (d, J = 4.51 Hz, 3 H) 3.14 (m,2 H) 3.63 (m, 1 H) 4.01 (m, 1 H) 4.29 (s, 3 H) 4.43 (m, 1 H) 7.15 (s, 1H) 7.39 (m, 2 H) 7.47 (m, 3 H) 8.13 (m, 1 H) 8.22 (s, 1 H)B94-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 6 H) 1.60(m, 2 H) 1.99 (m, 2 H) 2.52 (s, 2 H) 2.59 (m, 2 H) 2.75 (d, J = 4.51 Hz,3 H) 3.57 (m, 2 H) 3.71 (m, 1 H) 4.22 (s, 3 H) 7.11 (s, 1 H) 7.68 (m, 2H) 7.77 (m, 3 H) 8.11 (m, 1 H) 8.18 (s, 1 H) B93-X00-M03(C01)-D04 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.32 (s, 6 H) 1.60 (m, 2 H) 2.02 (m, 2 H) 2.62(s, 2 H) 2.75 (d, 3 H) 2.89 (m, 5 H) 3.55 (m, 2 H) 3.85 (m, 1 H) 4.30(s, 3 H) 7.16 (bd, 1 H) 8.13 (d, 1 H) 8.22 (s, 1 H) B89-X00-M03(C01)-D25¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J = 7.13 Hz, 3 H) 1.33 (s, 6 H)1.35-1.50 (m, 2 H) 1.93 (m, 2 H) 2.64 (s, 2 H) 2.86-3.06 (m, 2 H)3.84-4.00 (m, 3 H) 4.05 (q, J = 7.07 Hz, 2 H) 4.25 (d, J = 5.73 Hz, 2 H)4.33 (s, 3 H) 7.14 (s, 1 H) 8.23 (s, 1 H) 8.92 (t, J = 5.79 Hz, 1 H)B89-X00-M03(C01)-D138 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J = 7.13Hz, 3 H) 1.22 (s, 6 H) 1.42 (m, 2 H) 1.94 (m, 2 H) 2.62 (s, 2 H) 3.0 (m,5 H) 3.54 (m, 2 H) 3.63 (m, 2 H) 3.95 (m, 3 H) 4.05 (q, J = 7.07 Hz, 2H) 4.33 (s, 3 H) 7.14 (s, 1 H) 8.23 (s, 1 H) 8.92 (t, J = 5.79 Hz, 1 H)

In table XII below see the HPLC/Mass data for some representativecompounds of the invention

TABLE XII M + H Time Method B89-X00-M03(C01)-D05 444.23 2.07 2B89-X00-M03(C01)-D31 500.29 2.6 2 B89-X00-M03(C01)-D32 500.29 2.44 2B89-X00-M03(C01)-D33 498.24 2.85 2 B89-X00-M03(C01)-D136 541.32 1.73 2B89-X00-M03(C01)-D137 515.3 1.79 2 B89-X00-M03(C01)-D17 555.33 1.88 2B89-X00-M03(C01)-D76 541.32 2 2 B89-X00-M03(C01)-D78 486.28 2.29 2B89-X00-M03(C01)-D79 516.29 1.91 2 B89-X00-M03(C01)-D14 496.3 3.16 2B89-X00-M03(C01)-D80 486.28 2.21 2 B89-X00-M03(C01)-D44 519.28 2.49 2B89-X00-M03(C01)-D81 539.34 1.98 2 B89-X00-M03(C01)-D12 486.28 2.55 2B89-X00-M03(C01)-D25 467.24 2.66 2 B89-X00-M03(C01)-D82 486.28 2.27 2B89-X00-M03(C01)-D83 530.26 2.41 2 B89-X00-M03(C01)-D84 519.28 2.66 2B89-X00-M03(C01)-D85 487.27 2.18 2 B89-X00-M03(C01)-D60 548.29 2.83 2B89-X00-M03(C01)-D86 499.31 1.8 2 B89-X00-M03(C01)-D87 548.29 2.94 2B89-X00-M03(C01)-D88 510.31 3.37 2 B89-X00-M03(C01)-D89 481.26 2.51 2B89-X00-M03(C01)-D90 504.24 3.03 2 B89-X00-M03(C01)-D91 514.27 2.82 2B89-X00-M03(C01)-D92 498.28 2.25 2 B89-X00-M03(C01)-D93 540.32 2.49 2B89-X00-M03(C01)-D94 474.26 2.65 2 B89-X00-M03(C01)-D04 442.25 2.48 2B89-X00-M03(C01)-D95 502.27 2 2 B89-X00-M03(C01)-D34 548.29 2.8 2B89-X00-M03(C01)-D96 510.24 3.09 2 B89-X00-M03(C01)-D97 486.28 2.27 2B89-X00-M03(C01)-D45 519.28 2.52 2 B89-X00-M03(C01)-D98 500.29 2.43 2B89-X00-M03(C01)-D99 528.29 2.86 2 B89-X00-M03(C01)-D100 526.31 2.22 2B89-X00-M03(C01)-D06 472.26 2.15 2 B89-X00-M03(C01)-D101 514.31 2.62 2B89-X00-M03(C01)-D102 456.26 2.67 2 B89-X00-M03(C01)-D103 512.29 2.03 2B89-X00-M03(C01)-D104 486.28 2.27 2 B89-X00-M03(C01)-D105 512.2 2.15 2B89-X00-M03(C01)-D106 498.31 3.22 2 B89-X00-M03(C01)-D107 512.25 2.52 2B89-X00-M03(C01)-D108 615.33 2.98 2 B89-X00-M03(C01)-D109 561.32 3.4 2B89-X00-M03(C01)-D110 515.27 1.99 2 B89-X00-M03(C01)-D111 528.32 2.76 2B89-X00-M03(C01)-D112 533.29 2.76 2 B89-X00-M03(C01)-D113 512.29 2.27 2B89-X00-M03(C01)-D114 583.33 2.9 2 B89-X00-M03(C01)-D115 525.32 1.91 2B89-X00-M03(C01)-D116 539.34 1.95 2 B89-X00-M03(C01)-D117 514.31 2.64 2B89-X00-M03(C01)-D118 500.29 2.52 2 B89-X00-M03(C01)-D119 502.27 2.02 2B89-X00-M03(C01)-D120 482.28 3.06 2 B89-X00-M03(C01)-D121 553.32 2.32 2B89-X00-M03(C01)-D122 526.31 2.38 2 B89-X00-M03(C01)-D123 498.28 2 2B89-X00-M03(C01)-D124 456.26 2.25 2 B89-X00-M03(C01)-D125 602.26 3.64 2B89-X00-M03(C01)-D126 584.3 3.2 2 B89-X00-M03(C01)-D127 603.33 3.08 2B89-X00-M03(C01)-D128 565.35 1.99 2 B89-X00-M03(C01)-D129 527.34 1.91 2B89-X00-M03(C01)-D130 541.35 1.93 2 B89-X00-M03(C01)-D131 525.32 1.78 2B89-X00-M03(C01)-D132 616.36 2.25 2 B89-X00-M03(C01)-D133 603.33 3.37 2B89-X00-M03(C01)-D134 521.29 3.11 2 B89-X00-M03(C01)-D135 498.28 2.03 2

Example 33 Ethyl1-methyl-8-(pyrrolidin-3-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B99-X00-M00(C01)-D03]

A solution of 110 mg (0.27 mmol) of ethyl8-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatein a mixture dichoromethane-trifluoroacetic acid 9/1 was stirred at roomtemperature for 6 hours. The solvent was then removed in vacuo and theresulting oil taken up with dichloromethane and washed with aqueousNaHCO₃. The organic layer was dried over Na₂SO₄ and evaporated. Theresidue was triturated with diethylether giving 83 mg (60% yield) of thetitle compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98-2.11 (m, 1H) 2.22 (s, 1H) 2.77 (t,J=7.62 Hz, 2H) 2.92-3.02 (m, 2H) 3.14-3.55 (m, 4H) 4.31 (s, 3H)4.44-4.57 (m, 1H) 7.27 (s, 2H) 8.29 (s, 1H) 8.76 (s, 1H)

Analogously the following compound was prepared:

-   N,1-dimethyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B79-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.82 (m, 2H) 2.05-2.16 (m, 2H) 2.75(d, J=4.76 Hz, 3H) 2.75-2.80 (m, 2H) 2.97 (t, J=7.68 Hz, 2H) 3.01-3.09(m, 2H) 3.27-3.49 (m, 2H) 3.93-4.10 (m, 1H) 4.31 (s, 3H) 7.59 (s, 1H)8.07 (q, J=4.47 Hz, 1H) 8.26 (s, 1H) 8.44-8.63 (m, 1H) 8.69-8.90 (m,1H).

Example 341-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B79-X00-M00(C01)-D03]

To a solution of 1 g (2.4 mmol) of8-[(1-benzylpiperidin-4-yl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidein 90 mL of absolute ethanol 1 g of palladium on charcoal 10% w and 30mL of 98% formic acid were added. The resulting mixture was stirred at60° C. for 12 hours. The catalyst was then filtered on celite and thefiltrate evaporated. The crude was purified by chromatography on asilica gel column eluted with a mixture CH₂Cl₂-MeOH-Et₃N, giving 350 mg(45% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.77 (m, 2H) 2.04-2.17 (m, 2H) 2.75(t, J=7.56 Hz, 2H) 2.96 (t, J=7.56 Hz, 2H) 2.99-3.09 (m, 2H) 3.28-3.44(m, 2H) 3.93-4.08 (m, 1H) 4.31 (s, 3H) 7.25 (s, 1H) 7.31 (d, J=7.56 Hz,1H) 7.43 (s, 1H) 8.25 (s, 1H).

Example 358-[(1-formylpiperidin-4-yl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B169-X00-M00(C01)-D03

500 mg (1.53 mmol) of1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidewere dissolved in 10 mL of dimethylformamide, containing 253 mg (1.68mmol) of tert-butyldimethylsilyl chloride, 0.26 mL of triethylamine and7 mg of 4-dimethylaminopyridine (0.06 mmol), and the mixture stirred at35-40° C. for 25 hours under nitrogen. The mixture was then partitionedbetween dichloromethane and water, the organic layer was separated,washed with brine and dried over sodium sulfate. Evaporation of thevolatiles in vacuo afforded 435 mg (80% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.48 (m, 2H) 1.88-2.03 (m, 2H) 2.74(t, J=7.68 Hz, 2H) 2.77-2.87 (m, 1H) 2.95 (t, J=7.62 Hz, 2H) 3.10-3.20(m, 1H) 3.66-3.79 (m, 1H) 3.93-4.05 (m, 1H) 4.09-4.17 (m, 1H) 4.31 (s,3H) 7.13 (d, J=6.83 Hz, 1H) 7.23 (s, 1H) 7.44 (s, 1H) 8.01 (s, 1H) 8.23(s, 1H).

Example 368-(cyclopentylamino)-1-piperidin-4-yl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B73-X00-M00(C18)-D03]

500 mg (1.1 mmol) of1-(1-benzylpiperidin-4-yl)-8-(cyclopentylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidewere dissolved in 50 mL of acetic acid and 50 mg of PtO₂ were added. Themixture was submitted to hydrogenation at 60 psi at room temperature.After 12 hors the catalyst was filtered on celite and the filtrateevaporated. The residue was redissolved with dicholoromethane and washedwith aqueous NaHCO₃. The organic layer was dried over sodium sulfate andthe solvent removed under reduced pressure. The title compound (80%yield) was collected by filtration after trituration with diethylether.

Example 378-(cyclopentylamino)-N-hydroxy-N,1-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B73-X00-M00(C01)-D142]

To a suspension of 400 mg (1.14 mmol) of potassium8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatein 80 mL of dichloromethane and a few drops of dimethylformamide 0.11 mL(0.13 mmol) of oxalyl chloride were added at 0° C. The mixture wasstirred at room temperature for 6 hours and then evaporated, redissolvedin anhydrous dichloromethane and dropped into a solution of 344 mg (2.28mmol) of N-methylhydroxylamine hydrochloride and 0.33 mL oftriethylamine in 20 mL of the same solvent, cooled to 0° C. After 4hours the mixture was washed with a saturated solution of sodiumhydrogencarbonate, dried over sodium sulfate and evaporated to dryness.The residue was triturated with diethylether and filtered to give 780 mg(60% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.61 (m, 4H) 1.64-1.78 (m, 2H)1.87-2.01 (m, 2H) 2.67-2.89 (m, 4H) 3.35 (s, 3H) 4.11-4.23 (m, 1H) 4.31(s, 3H) 7.06 (d, J=6.58 Hz, 1H) 8.20 (s, 1H) 9.88 (s, 1H).

Analogously, but employing the suitable hydroxylamino derivatives, thefollowing compounds were prepared:

-   N-cyclohexyl-8-(cyclopentylamino)-N-hydroxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B73-X00-M00(C01)-D29]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96-2.04 (m, 18H) 2.67-2.81 (m, 4H)4.04-4.45 (m, 2H) 4.30 (s, 3H) 6.97-7.10 (m, 1H) 8.20 (s, 1H) 9.45 (s,1H);

-   N-benzyl-8-(cyclopentylamino)-N-hydroxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B73-X00-M00(C01)-D28]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.61 (m, 4H) 1.64-1.79 (m, 2H)1.87-2.00 (m, 2H) 2.70-2.88 (m, 4H) 4.08-4.22 (m, 1H) 4.31 (s, 3H) 5.01(s, 2H) 7.06 (d, J=6.58 Hz, 1H) 7.22-7.43 (m, 5H) 8.21 (s, 1H) 9.89 (s,1H).

Example 388-anilino-N-hydroxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B04-X00-M00(C01)-D05]

To a solution of 260 mg (0.81 mmol) of8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid in 50 mL of anhydrous dimethylformamide 111 mg ofN-hydroxybenzotriazole (0.81 mmol), 0.16 mL of N-methylmorpholine, 205mg (1.07 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride and 585 mg (2.13 mmol) of triphenylmethylhydroxylaminewere added consecutively. After 48 hours at room temperature the solventwas removed under reduced pressure and the residue taken up withdichoromethane and washed with water. The organic layer was then driedover sodium sulfate and evaporated. The crude was treated with 10 mL ofa mixture dichloromethane-trifluoroacetic acid and after 4 hours thevolatiles were removed in vacuo. The residue was redissolved withdichoromethane and washed with aqueous NaHCO₃ and the product purifiedby chromatography on a silica gel column, eluted with CH₂Cl₂—CH₃COCH₃4/1, to give 180 mg (66% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.80-2.91 (m, 2H) 2.93-3.06 (m, 2H) 4.33(s, 3H) 6.97 (tt, J=7.35, 1.07 Hz, 1H) 7.31 (dd, J=8.47, 7.38 Hz, 2H)7.72 (dd, J=8.66, 1.10 Hz, 2H) 8.42 (s, 1H) 8.91 (s, 1H) 9.52 (s, 1H)10.93 (s, 1H)

Example 398-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B73-X00-M00(C01)-D03]

1.0 g (2.6 mmol) of ethyl8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatewere dissolved in a mixture of 100 mL of methanol and 100 mL of ammoniumhydrate 33%. The solution was stirred in a close bottle at 60° C. for 4hours. The resulting precipitate was collected giving 0.5 g (54% yield)of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.99 (m, 4H) 4.25 (s, 3H) 7.31 (s, 1H)7.51 (s, 1H) 8.47 (s, 1H)

Example 401-methyl-8-[(1-methylpiperidin-4-yl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B90-X00-M00(C01)-D03]

8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(0.10 g, 0.28 mmol) and 1-methylpiperidin-4-amine (0.19 g, 1.7 mmol)were heated at 80° C. under nitrogen for 3 hours. The mixture wasconcentrated under reduced pressure and the residue was purified bychromatography on a silica gel column (eluant:dichloromethane/ethanol/ammonium hydroxide 90/10/1) to give 0.047 mg of1-methyl-8-[(1-methylpiperidin-4-yl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(50% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (m, 2H) 1.91 (m, 2H) 2.06 (m, 2H)2.4 (s, 3H) 2.73 (m, 2H) 2.83 (m, 2H) 2.94 (m, 2H) 3.70 (m, 1H) 4.30 (s,3H) 7.01 (m, 1H) 7.25 (s, 1H) 7.44 (s, 1H) 8.29 (s, 1H)

Example 41[8-(cyclohexylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone[B27-X00-M01(C01)-D07] and[8-(cyclohexylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone[B27-X00-M01(C01)-D07]

Step 1. 6-[(dimethylamino)methylene]-2-ethoxycyclohex-2-en-1-one

3.4 g (0.02 mmol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 30 mLof dry dimethylformamide and 30 mL (0.05 mmol) of dimethylformamidedimethyl acetale were added. The solution was stirred at 60° C. for 2hours. The solvent was then evaporated under vacuum, the residuetriturated with diethyl ether and collected by filtration to give 6.6 gof the title compound (80% yield).

Step 2. 2-(benzylthio)-8-ethoxy-5,6-dihydroquinazoline

To a solution of 2.0 g (0.01 mol) of6-[(dimethylamino)methylene]-2-ethoxycyclohex-2-en-1-one in 20 mL ofdimethylformamide 2.6 g of S-benzylisothiourea (2 eq. mol.) were added.The reaction mixture was stirred at 95° C. for 4 hours. The solvent wasthen evaporated under reduced pressure and the crude purified bychromatography on a silica gel column (eluant dichloromethane/methanol9/1) leading 1.5 g (50% yield) of the title compound.

Step 3. 2-(benzylthio)-6,7-dihydroquinazolin-8(5H)-one

1.5 g (5 mmol) of 2-(benzylthio)-8-ethoxy-5,6-dihydroquinazoline weredissolved in 50 mL of acetic acid and 3 mL of water. The solution wasstirred at refluxing temperature for 4 hours. The solvent was thenremoved under vacuum, the residue partitioned between dichloromethaneand a NaHCO₃ saturated solution. The organic layer was dried overanhydrous Na₂SO₄ and concentrated, giving 1.0 g (74% yield) of the titlecompound.

Step 4.1-[2-(benzylthio)-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl]-2-phenylethane-1,2-dione

To a solution of 0.22 g (0.81 mmol) of2-(benzylthio)-6,7-dihydroquinazolin-8(5H)-one in 5 mL of drytetrahydrofuran cooled to −50° C., 0.10 g of sodium hydride 60% inmineral oil were added. The resulting suspension was maintained at thesame temperature for 30 minutes and then 0.59 mL of ethylα-oxobenzeneacetate (PhCOCOOEt) were added and the reaction mixtureallowed to come to room temperature. After 16 hours the mixture waspartitioned between water and ethyl acetate and the organic layer wasdried over Na₂SO₄ and evaporated to dryness. The residue was purified bychromatography on a silica gel column (eluant hexane/ethyl acetate 7/3)giving 0.22 g (68% yield) of the title compound.

Step 5.[8-(benzylthio)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone[B05-X04-M00(C01)-D07]

0.22 g (0.55 mmol) of1-[2-(benzylthio)-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl]-2-phenylethane-1,2-dionewere dissolved in 6 mL of ethanol and 0.03 g (0.66 mmol) of methylhydrazine were added. The reaction mixture was maintained under stirringat refluxing temperature for 5 hours. After that time the solvent wasremoved under reduced pressure, the residue redissolved withdichloromethane and washed with water. The organic layer was dried overNa₂SO₄ and concentrated, giving 0.16 g of the title compound (70%yield).

Step 6.[8-(benzylsulfonyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone[B05-X05-M00(C01)-D07]

To a solution of 70 mg (0.17 mmol) of[8-(benzylthio)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanonein 3 mL of dichloromethane, 115 mg (0.34 mmol) of m-chloroperbenzoicacid were added. The reaction mixture was maintained at room temperaturefor 1 hour. The solution was then washed with aqueous NaHCO₃ and theorganic layer was dried over Na₂SO₄ and evaporated in vacuo, giving 70mg (93% yield) of the title compound.

Step 7.[8-(cyclohexylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone[B27-X00-M00(C01)-D07] and[8-(cyclohexylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone[B27-X00-M01(C01)-D07]

83 mg (0.19 mmol) of[8-(benzylsulfonyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanonewere dissolved in 3 mL of dimethylsulfoxide and cyclohexylamine (0.033mL, 0.29 mmol) and the solution was heated at 100° C. under stirring for16 hours. The solvent was then removed under reduced pressure and thecrude purified by chromatography on a silica gel column (eluantdichloromethane/acetone) giving 31 mg of[8-(cyclohexylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanoneand 15 mg of[8-(cyclohexylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone(70% yield overall).

-   B27-X00-M00(C01)-D07

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-2.00 (5m, 11H) 2.61 (m, 2H) 2.66(m, 2H) 3.80 (s, 3H) 7.17 (bs, 1H) 7.34-7.37 (m, 3H) 7.41-7.51 (m, 3H)8.27 (s, 1H);

-   B27-X00-M01(C01)-D07

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-2.20 (5m, 11H) 4.02 (bs, 3H) 6.69(m, 1H) 7.37-7.58 (2m, 6H) 7.93 (bs, 1H) 8.83 (bs, 1H).

Example 42 Ethyl1-methyl-8-(pyridin-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B15-X00-M00(C01)-D01]

Palladium acetate [Pd(OAc)₂] (15.3 mg, 0.07 mmol, 10%), (±)-BINAP (42.6mg, 0.07 mmol, 10%) and dimethylformamide (12 mL) were charged in around-bottom flask flushed with argon. The mixture was stirred underargon for 30 minutes. Then 2-aminopyridine (70.4 mg, 0.75 mmol), ethyl8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(250 mg, 0.65 mmol), potassium carbonate (1.89 g, 13.67 mmol) anddimethylformamide (5 mL) were added. The resulting mixture was stirredat room temperature for 1 hour and then heated to 120° C. in an oil bathunder argon with good stirring for 18 hours.

After cooling to room temperature, the reaction mixture was poured intowater and extracted with dichloromethane. The organic extracts werewashed with brine and dried over Na₂SO₄. The solvent was removed undervacuum, the crude solid was taken up with diethyl ether, filtered,washed with diethyl ether and purified by flash chromatography on silicagel (eluant: dichloromethane/methanol 97.5:2.5) to afford 145 mg (63.8%yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 3.0 (m, 4H) 4.3(q, J 7.2 Hz, 2H) 4.4 (s, 3H) 7.0 (ddd, J 7.2, 4.9, 1.0 Hz, 1H) 7.8(ddd, 1H) 8.2 (d, J 8.4 Hz, 1H) 8.3 (ddd, J 4.8, 2.0, 0.9 Hz, 1H) 8.5(s, 1H) 9.9 (s, 1H).

By working according to the above method, the following compounds wereprepared:

-   ethyl    8-[(3,5-dichlorophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B14-X00-M00(C01)D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 4.3(q, J 7.2 Hz, 2H) 4.4 (s, 3H) 7.1 (m, 1H) 7.4 (m, 2H) 8.5 (s, 1H) 10 (s,1H);

-   ethyl    8-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B16-X00-M00(C01)D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 3.8(s, 3H) 4.3 (q, J 7.2 Hz, 2H) 4.4 (s, 3H) 6.8 (s, 1H) 7.6 (s, 1H) 7.8(s, 1H) 8.5 (s, 1H) 9.9 (s, 1H);

-   ethyl    8-[(4-hydroxyphenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B18-X00-M00(C01)D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 4.3(m, 5H) 6.7 (d, J 8.8 Hz, 2H) 7.4 (d, J 8.9 Hz, 2H) 8.3 (s, 1H) 9.1 (s,1H) 9.2 (s, 1H);

-   ethyl    8-(1H-imidazol-1-ylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B21-X00-M00(C01)D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (m, 3H) 2.9 (m, 4H) 4.3 (d, J 7.1Hz, 2H) 4.4 (s, 3H) 7.1 (s, 1H) 7.6 (d, J 8.9 Hz, 2H) 7.7 (s, 1H) 7.9(d, J 8.9 Hz, 2H) 8.2 (s, 1H) 8.5 (s, 1H) 9.7 (s, 1H);

-   ethyl    1-methyl-8-(1,3-thiazol-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B86-X00-M00(C01)D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (m, 3H) 3.0 (m, 4H) 4.3 (q, J 7.1Hz, 2H) 4.4 (s, 3H) 7.1 (d, J 3.5 Hz, 1H) 7.5 (d, J 3.7 Hz, 1H) 8.6 (s,1H) 11.6 (s, 1H);

-   ethyl    1-methyl-8-(1H-pyrazol-3-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B77-X00-M00(C01)D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 4.3(q, J 7.1 Hz, 2H) 4.4 (s, 3H) 6.5 (s, 1H) 7.6 (s, 1H) 8.4 (s, 1H) 9.6(s, 1H) 12.2 (s, 1H);

-   ethyl    1-methyl-8-[(4-morpholin-4-ylphenyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B19-X00-M00(C01)D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 3.1(m, 4H) 3.8 (m, 4H) 4.3 (q, J 7.2 Hz, 2H) 4.3 (s, 3H) 6.9 (d, J 9.0 Hz,2H) 7.6 (d, J 9.0 Hz, 2H) 8.4 (s, 1H) 9.3 (s, 1H);

-   ethyl    8-{[4-(ethoxycarbonyl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B87-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 6H) 3.0 (m, 4H) 4.3(m, 4H) 4.4 (s, 3H) 7.9 (m, 4H) 8.5 (s, 1H) 10.0 (s, 1H);

-   ethyl    8-{[4-(N,N-diethylamino)phenyl]amino}-}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B17-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.1 (t, J 7.0 Hz, 6H) 1.3 (t, J 7.1 Hz,3H) 2.9 (m, 4H) 3.3 (m, 4H) 4.3 (q, J 7.1, 7.1 Hz, 2H) 4.3 (s, 3H) 6.7(d, J 9.1 Hz, 2H) 7.4 (d, J 9.0 Hz, 2H) 8.3 (s, 1H) 9.1 (s, 1H);

-   ethyl    8-{[4-(acetylamino)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B22-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.0 (s, 3H) 2.9(m, 4H) 4.3 (q, J 7.1 Hz, 2H) 4.4 (s, 3H) 7.5 (d, J 9.0 Hz, 2H) 7.6 (d,J 9.0 Hz, 2H) 8.4 (s, 1H) 9.4 (s, 1H) 9.8 (s, 1H);

-   ethyl    8-{[3-(hydroxymethyl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B11-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 4.3(q, J 7.1 Hz, 2H) 4.4 (s, 3H) 4.5 (s, 2H) 6.9 (m, 1H) 7.3 (t, J 7.8 Hz,1H) 7.5 (m, 1H) 7.8 (s, 1H) 8.4 (s, 1H) 9.5 (s, 1H);

-   ethyl    8-[(4-methoxyphenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B68-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 3.7(s, 3H) 4.3 (q, J 7.1 Hz, 2H) 4.3 (s, 3H) 6.9 (d, J 9.0 Hz, 2H) 7.6 (d,J 9.0 Hz, 2H) 8.4 (s, 1H) 9.3 (s, 1H);

-   ethyl    8-{[(4-Bromo-3-chloro)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B88-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.3 (t, J 7.1 Hz, 3H) 2.9 (m, 4H) 4.3(q, J 7.1 Hz, 2H) 4.4 (s, 3H) 7.6 (dd, J 8.8, 2.4 Hz, 1H) 7.7 (d, J 8.8Hz, 1H) 8.2 (d, J 2.4 Hz, 1H) 8.5 (s, 1H) 9.9 (s, 1H);

-   ethyl    8-{[3-bromo-5-(trifluoromethyl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B115-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.1 Hz, 3H) 2.95 (m, 4H) 4.31(q, J=7.2 Hz, 2H) 4.39 (s, 3H) 7.49 (s, 1H) 8.10 (s, 1H) 8.36 (s, 1H)8.54 (s, 1H) 10.11 (s, 1H);

-   ethyl    8-[4-(4-methyl-piperazin-1-yl)-3-(hydroxymethyl)phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B116-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.07 Hz, 3H) 2.28 (s, 3H)2.42-2.61 (m, 4H) 2.79-2.88 (m, 6H) 2.98 (t, J=7.80 Hz, 2H) 4.31 (q,J=7.15 Hz, 2H) 4.36 (s, 3H) 4.56 (d, J=5.24 Hz, 2H) 5.06 (t, J=5.30 Hz,1H) 7.03 (d, J=8.66 Hz, 1H) 7.50 (dd, 1H) 7.81 (d, J=2.68 Hz, 1H) 8.39(s, 1H) 9.42 (s, 1H);

-   ethyl    1-methyl-8-{[4-(morpholin-4-ylmethyl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B102-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.13 Hz, 3H) 2.35 (s, 4H)2.86 (t, J=7.62 Hz, 2H) 2.99 (t, J=7.80 Hz, 2H) 3.42 (s, 2H) 3.55-3.61(m, 4H) 4.31 (q, J=7.07 Hz, 2H) 4.37 (s, 3H) 7.24 (d, J=8.41 Hz, 2H)7.66 (d, J=8.41 Hz, 2H) 8.42 (s, 1H) 9.52 (s, 1H);

-   ethyl    1-methyl-8-({4-[(1-methylpiperidin-4-yl)oxy]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B103-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (t, 3H) 2.09 (m, 4H) 2.86 (m, 5H)2.98 (t, 2H) 3.37 (m, 5H) 4.30 (q, 2H) 4.34 (s, 3H) 7.03 (m, 2H) 7.61(m, 2H) 8.39 (s, 1H) 9.40 (s, 1H);

-   ethyl    1-methyl-8-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B104-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, 3H) 2.21 (m, 3H) 2.40 (m, 8H)2.86 (t, 2H) 2.99 (t, 2H) 3.44 (s, 2H) 4.30 (q, 2H) 4.39 (s, 3H) 6.91(m, 1H) 7.24 (m, 1H) 7.56 (m, 1H) 7.75 (dd, 1H) 8.43 (m, 1H) 9.54 (s,1H);

-   ethyl    8-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B109-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, 3H) 2.28 (s, 3H) 2.85 (t, 2H)2.99 (m, 6H) 4.30 (q, 2H) 4.37 (s, 3H) 7.01 (t, 1H) 7.35 (dd, 1H) 7.64(dd, 1H) 8.42 (m, 1H) 9.56 (s, 1H);

-   ethyl    8-[(4-chlorophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B112-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, 3H) 2.86 (t, 2H) 2.99 (t, 2H)4.30 (q, 2H) 4.37 (s, 3H) 7.38 (d, 2H) 7.74 (d, 2H) 8.45 (s, 1H) 9.70(s, 1H);

-   ethyl    8-{[4-(hydroxymethyl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B114-X00-M00(C01)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, 3H) 2.86 (t, 2H) 2.99 (t, 2H)4.30 (q, 2H) 4.37 (s, 3H) 4.45 (s, 2H) 7.27 (d, 2H) 7.65 (d, 2H) 8.42(s, 1H) 9.50 (s, 1H).

Example 431-Methyl-8-(pyridin-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B15-X00-M00(C01)-D03]

To a solution of ethyl1-methyl-8-(pyridin-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(220 mg, 0.63 mmol) in methanol (250 mL), 33% aqueous ammonium hydroxide(100 mL) was added and the solution was stirred at 65° C. for 8 hours.

By concentrating the solution, the final compound that precipitated wascollected by suction filtration, washed with water and crystallizedtwice from methanol containing sodium hydroxide, and dried at 40° C.under vacuum. There were thus obtained 60 mg of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ 3.0 (m, 4H) 4.4 (s, 3H) 7.0 (ddd, J 7.2,4.9, 1.0 Hz, 1H) 7.3 (s, 1H) 7.5 (s, 1H) 7.8 (ddd, 1H) 8.2 (d, J 8.4 Hz,1H) 8.3 (ddd, J 4.8, 2.0, 0.9 Hz, 1H) 8.5 (s, 1H) 9.9 (s, 1H)

By working according to the same procedure, the following compounds wereprepared:

-   8-[(3,5-dichlorophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B14-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.0 (m, 4H) 4.4 (s, 3H) 7.1 (t, J 1.8Hz, 1H) 7.3 (s, 1H) 7.5 (s, 1H) 7.9 (d, J 1.8 Hz, 2H) 8.5 (s, 1H) 10.0(s, 1H);

-   8-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B16-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 3.8 (s, 3H) 4.3 (s, 3H) 6.8(s, 1H) 7.3 (s, 1H) 7.5 (s, 1H) 7.6 (s, 1H) 7.8 (s, 1H) 8.5 (s, 1H) 9.9(s, 1H);

-   8-[(4-hydroxyphenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B18-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 4.3 (s, 3H) 6.7 (d, J 8.8Hz, 2H) 7.2 (s, 1H) 7.4 (d, J 8.9 Hz, 2H) 7.5 (s, 1H) 8.3 (s, 1H) 9.1(s, 1H) 9.2 (s, 1H);

-   8-{[4-(1H-imidazol-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B21-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 4.4 (s, 3H) 7.1 (s, 1H) 7.3(s, 1H) 7.5 (s, 1H) 7.6 (d, J 8.9 Hz, 2H) 7.7 (t, J 1.2 Hz, 1H) 7.9 (d,J 9.0 Hz, 2H) 8.2 (s, 1H) 8.4 (s, 1H) 9.7 (s, 1H);

-   1-methyl-8-(thiazol-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B86-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.0 (m, 4H) 4.4 (s, 3H) 7.1 (d, J 3.7Hz, 1H) 7.3 (s, 1H) 7.5 (d, J 3.7 Hz, 1H) 7.5 (s, 1H) 8.6 (s, 1H) 11.8(s, 1H);

-   1-methyl-8-(1H-pyrazol-3-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B77-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 4.3 (s, 3H) 6.5 (bs, 1H)7.25 (s, 1H) 7.45 (s, 1H) 7.6 (bs, 1H) 8.4 (s, 1H) 9.9 (s, 1H);

-   8-{[4-(N-morpholino)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B19-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 3.1 (m, 4H) 3.8 (m, 4H) 4.3(s, 3H) 6.9 (d, J 9.1 Hz, 2H) 7.2 (s, 1H) 7.5 (s, 1H) 7.6 (d, J 9.0 Hz,2H) 8.4 (s, 1H) 9.3 (s, 1H);

-   8-{[4-(diethylamino)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B17-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.1 (t, J 7.0 Hz, 6H) 2.9 (m, 4H) 3.3(m, 4H) 4.3 (s, 3H) 6.7 (d, J 9.0 Hz, 2H) 7.2 (s, 1H) 7.4 (m, J 9.0 Hz,1H) 7.4 (d, J 9.0 Hz, 2H) 8.3 (s, 1H) 9.1 (s, 1H);

-   8-{[4-(acetylamino)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B22-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.0 (s, 3H) 2.9 (m, 4H) 4.3 (s, 3H) 7.3(s, 1H) 7.5 (s, 1H) 7.5 (d, J 8.9 Hz, 2H) 7.6 (d, J 9.0 Hz, 2H) 8.4 (s,1H) 9.4 (s, 1H) 9.8 (s, 1H);

-   8-{[3-(hydroxymethyl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B11-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 4.3 (s, 3H) 4.5 (s, 2H) 5.2(s, 1H) 6.9 (d, J 8.0 Hz, 1H) 7.2 (m, 2H) 7.5 (s, 1H) 7.5 (dd, J 8.1,1.4 Hz, 1H) 7.8 (t, J 1.8 Hz, 1H) 8.4 (s, 1H) 9.5 (s, 1H);

-   8-[(4-methoxyphenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B68-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 3.7 (s, 3H) 4.3 (s, 3H) 6.9(d, J 9.1 Hz, 2H) 7.3 (s, 1H) 7.5 (s, 1H) 7.6 (d, J 9.0 Hz, 2H) 8.4 (s,1H) 9.3 (s, 1H);

-   8-{[(4-Bromo-3-chloro)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B88-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 4.4 (s, 3H) 7.3 (s, 1H) 7.5(s, 1H) 7.6 (dd, J 8.8, 2.4 Hz, 1H) 7.7 (d, J 8.8 Hz, 1H) 8.2 (d, J 2.4Hz, 1H) 8.5 (s, 1H) 9.9 (s, 1H);

-   8-[4-(4-methyl-piperazin-1-yl)-3-(hydroxymethyl)phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B116-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29 (s, 3H) 2.45-2.61 (m, 4H) 2.73-2.87(m, 6H) 2.99 (t, J=7.56 Hz, 2H) 4.34 (s, 3H) 4.56 (d, J=5.24 Hz, 2H)5.06 (t, J=5.37 Hz, 1H) 7.03 (d, J=8.66 Hz, 1H) 7.26 (s, 1H) 7.46 (s,1H) 7.50 (dd, J=8.23, 2.99 Hz, 1H) 7.83 (d, J=2.68 Hz, 1H) 8.38 (s, 1H)9.40 (s, 1H);

-   8-[4-(4-methyl-piperazin-1-yl)-3-(hydroxymethyl)phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic    acid methylamide [B116-X00-M00(C01)-D04]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28 (s, 3H) 2.45-2.55 (m, 4H) 2.75 (d,J=4.63 Hz, 3H) 2.81 (t, J=7.19 Hz, 2H) 2.83 (t, J=4.63 Hz, 4H) 2.99 (t,J=7.56 Hz, 2H) 4.34 (s, 3H) 4.56 (d, J=5.24 Hz, 2H) 5.05 (t, J=5.37 Hz,1H) 7.03 (d, J=8.54 Hz, 1H) 7.50 (d, J=8.41, 2.56 Hz, 1H) 7.83 (d,J=2.68 Hz, 1H) 8.07 (q, J=4.63 Hz, 1H) 8.37 (s, 1H) 9.40 (s, 1H);

-   8-[4-(4-methyl-piperazin-1-yl)-3-(bromo)phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    trihydrochloride [B117-X00-M00(C01)-D03

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.83 (m, 2H) 2.88 (d, J=4.68 Hz, 3H)3.01 (m, 4H) 3.19 (m, 2H) 3.53 (m, 2H) 4.37 (s, 3H) 7.23 (m, 1H) 7.29(s, 1H) 7.46 (s, 1H) 7.63 (m, 1H) 8.21 (m, 1H) 8.44 (s, 1H) 9.67 (s, 1H)10.13 (s, 1H);

-   8-[3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B104-X00-M00(C01)-D03

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3H) 2.44 (s, 4H) 2.78-3.03 (m,4H) 3.04-3.40 (m, 4H) 3.45 (s, 2H) 4.37 (s, 3H) 6.90 (d, J=7.32 Hz, 1H)7.25 (t, J=7.68 Hz, 1H) 7.27 (s, 1H) 7.46 (s, 1H) 7.57 (dd, J=7.68, 1.59Hz, 1H) 7.76 (t, J=1.77 Hz, 1H) 8.42 (s, 1H) 9.52 (s, 1H);

-   8-{[(3-hydroxy)-5-trifluoromethyl]phenylamino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B118-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.77-3.07 (m, 4H) 3.84 (s, 3H) 4.35 (s,3H) 6.84 (s, 1H) 7.28 (s, 1H) 7.47 (s, 1H) 7.57 (s, 1H) 7.85 (s, 1H)8.49 (s, 1H) 9.86 (s, 1H);

-   8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic    acid methylamide [B10-X00-M00(C01)-D04]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.75 (d, J=4.76 Hz, 3H) 2.81 (t, J=7.68Hz, 2H) 2.85 (d, J=4.39 Hz, 3H) 2.94-3.07 (m, 4H) 3.11-3.25 (m, 2H) 3.51(d, J=11.83 Hz, 2H) 3.73 (d, J=13.66 Hz, 2H) 4.33 (s, 3H) 6.99 (d,J=9.15 Hz, 2H) 7.60 (d, J=9.02 Hz, 2H) 8.08 (q, J=4.67 Hz, 1H) 8.37 (s,1H) 9.40 (s, 1H) 10.36 (s, 1H);

-   8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic    acid methylamide [B04-X00-M00(C01)-D04]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.72 (d, J=4.76 Hz, 3H) 2.79 (t, J=7.68Hz, 2H) 2.97 (t, J=7.68 Hz, 2H) 4.31 (s, 3H) 6.94 (t, J=7.38 Hz, 1H)7.21-7.32 (m, 2H) 7.68 (d, J=7.56 Hz, 2H) 8.06 (q, J=4.35 Hz, 1H) 8.38(s, 1H) 9.48 (s, 1H).

Example 441-Methyl-8-(pyridin-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidehydrochloride

To a solution of1-methyl-8-(pyridin-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidein a 1:1 mixture of methanol and dichloromethane, 4 N HCl in dioxane (1mL) was added. After 1 hour at room temperature the solvent was removedunder vacuum and the solid was triturated with diethyl ether affordingthe title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.0 (m, 4H) 4.4 (s, 3H) 7.3 (m, 2H) 7.5(s, 1H) 7.8 (d, J 8.8 Hz, 1H) 8.2 (t, J 7.7 Hz, 1H) 8.4 (dd, J 5.9, 1.0Hz, 2H) 8.6 (s, 1H) 11.6 (s, 1H).

By working according to this method, the following compounds wereprepared:

-   1-methyl-8-(thiazol-2-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.0 (m, 4H) 4.4 (s, 3H) 7.1 (d, J 3.7Hz, 1H) 7.3 (s, 1H) 7.5 (d, J 3.7 Hz, 1H) 7.5 (s, 1H) 8.6 (s, 1H) 11.8(s, 1H);

-   8-[4(N-Methylpiperazino)-3-chlorophenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    trichlorohydrate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.1 (m, 15H) 4.4 (s, 3H) 7.2 (d, J 8.9Hz, 1H) 7.3 (s, 1H) 7.5 (s, 1H) 7.6 (dd, J 8.8, 2.4 Hz, 1H) 8.0 (d, J2.6 Hz, 1H) 8.4 (s, 1H) 9.7 (s, 1H) 10.5 (s, 1H);

-   8-[4(N-Methylpiperazino)-3-bromophenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    trichlorohydrate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.1 (m, 15H) 4.4 (s, 3H) 7.2 (d, J 8.8Hz, 1H) 7.3 (s, 1H) 7.5 (s, 1H) 7.6 (dd, J 8.6, 2.4 Hz, 1H) 8.0 (d, J2.6 Hz, 1H) 8.2 (s, 1H) 9.7 (s, 1H) 10.5 (s, 1H);

-   N-benzyl-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    (L)-tartrate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.40 (s, 3H) 2.70 (m, 4H) 2.80 (t,J=7.62 Hz, 2H) 3.00 (t, J=7.62 Hz, 2H) 3.14 (m, 4H) 4.20 (s, 2H) 4.34(s, 3H) 4.43 (d, J=6.34 Hz, 2H) 6.93 (d, J=9.15 Hz, 2H) 7.27 (m, 5H)7.55 (d, J=9.02 Hz, 2H) 8.35 (s, 1H) 8.69 (t, J=6.34 Hz, 1H) 9.28 (s,1H);

-   1-methyl-8-[(4-morpholin-4-ylphenyl)amino]-N-[(1R)-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (m, 3H) 2.97 (m, 4H) 3.21 (m, 4H)3.84 (m, 4H) 4.37 (m, 3H) 5.15 (m, 1H) 7.28 (m, 7H) 7.63 (m, 2H) 8.40(m, 1H) 8.44 (m, 1H) 9.50 (m, 1H);

-   N-(3-fluorobenzyl)-1-methyl-8-[(4-morpholin-4-ylphenyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.91 (m, J=73.53 Hz, 4H) 3.16 (m, 4H)3.81 (m, 4H) 4.35 (s, 3H) 4.43 (m, 2H) 7.07 (m, 6H) 7.61 (m, 2H) 8.37(m, 1H) 8.80 (m, 1H) 9.44 (m, 1H);

-   N-(3-fluorobenzyl)-1-methyl-8-[(4-morpholin-4-ylphenyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    methanesulfonate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (s, 3H) 3.00 (s, 4H) 3.17 (s, 4H)3.80 (s, 4H) 4.35 (s, 3H) 4.43 (m, 2H) 7.07 (m, 6H) 7.61 (m, 2H) 8.37(m, 1H) 8.80 (m, 1H) 9.46 (m, 1H).

Example 458-anilino-N-(2-hydroxyethyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B04-X00-M00(C01)-D06]

To a suspension of 0.30 g (0.86 mmol) of ethyl8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatein a mixture of 10 mL of methanol and 10 mL of dimethylformamide, 5 mLof ethanolamine were added. The mixture was heated in a close bottleunder stirring at 65° C. After 5 hours the solvent was removed, theresidue redissolved with dichloromethane and washed with water. Theorganic layer was dried over Na₂SO₄ and evaporated. The residue wastriturated with diethyl ether and the product collected by filtration(60% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.7-3.0 (2m, 4H) 3.47 (m, 4H) 4.32 (s,3H) 4.71 (t, 1H) 6.94-7.67 (3m, 5H) 7.91 (t, J 5.73 Hz, 1H) 8.38 (bs,1H) 9.48 (bs, 1H).

By working analogously the following compound was prepared:

-   8-anilino-N,1-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B04-X00-M00(C01)-D04]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.72 (d, J 4.76 Hz, 3H) 2.79 (t, J 7.68Hz, 2H) 2.97 (t, J 7.68 Hz, 2H) 4.31 (s, 3H) 6.94 (t, J 7.38 Hz, 1H)7.28 (m, 2H) 7.68 (d, J 7.56 Hz, 2H) 8.06 (q, J 4.35 Hz, 1H) 8.38 (s,1H) 9.48 (s, 1H).

Example 468-[(4-methoxy-3-chlorophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B20-X00-M00(C01)-D03]

Pd(OAc)₂ (20 mg, 0.09 mmol, 10%), (±)-BINAP (55 mg, 0.09 mmol, 10%) anddimethylformamide (15 mL) were charged in a round-bottom flask flushedwith argon. The mixture was stirred under argon for 30 minutes. Then3-chloro-p-anisidine (153 mg, 0.97 mmol),8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(300 mg, 0.84 mmol), K₂CO₃ (2.45 g, 17.8 mmol) and dimethylformamide (6mL) were added. The resulting mixture was stirred at room temperaturefor 1 hour and then heated to 120° C. in an oil bath under argon withgood stirring for 18 hours.

After cooling to room temperature, the reaction mixture was poured intowater (300 mL) and extracted with dichloromethane (5×60 mL) The organicextracts were washed with water (2×20 mL) and dried over anhydrousNa₂SO₄. The solvent was removed under vacuum, the crude solid was takenup with diethyl ether, filtered, washed with diethyl ether and purifiedby flash chromatography on silica gel (eluant: dichloromethane/methanol97.5:2.5) to afford 95 mg of pure title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.9 (m, 4H) 3.8 (s, 3H) 4.3 (s, 3H) 7.1(d, J 9.0 Hz, 1H) 7.3 (s, 1H) 7.5 (s, 1H) 7.5 (dd, J 9.0, 2.6 Hz, 1H)7.9 (d, J 2.6 Hz, 1H) 8.4 (s, 1H) 9.5 (s, 1H)

By working according to the same procedure the following compound wasprepared:

-   8-[4(N-Methyl-N-piperazinyl)-3-chlorophenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B13-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.3 (s, 3H) 2.5 (m, 4H) 2.9 (m, 8H) 4.4(s, 3H) 7.1 (d, J 8.8 Hz, 1H) 7.3 (s, 1H) 7.5 (s, 1H) 7.5 (dd, J 8.8,2.4 Hz, 1H) 8.0 (d, J 2.6 Hz, 1H) 8.4 (s, 1H) 9.6 (s, 1H).

Example 478-[(4-methoxybenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B60-X00-M00(C01)-D03]

To a solution of8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(244 mg, 1.0 mmol) in a mixture of glacial acetic acid/methanol/water(1:1:1) (30 mL) in a round-bottom flask were added p-methoxybenzaldehyde(0.44 mL, 450 mg, 3.0 mmol) and then 85% sodium cyanoborohydride (210mg, 2.0 mmol). The solution was stirred at room temperature for 7 hours.At that time further amount of aldehyde (0.44 mL) and sodiumcyanoborohydride (210 mg) were added and stirring was continuedovernight.

The reaction mixture was poured into ice-water (200 mL), the pH wasadjusted to 10 by addition of saturated sodium carbonate and thesolution extracted with ethyl acetate (4×20 mL) The collected organicextracts were washed with brine until neutral, with water and dried overNa₂SO₄.

Evaporation of the solvent under vacuum left a yellow solid residue thatwas purified by flash chromatography on silica gel (eluant:dichloromethane/methanol 95:5) to yield 250 mg of yellow pure compound.Crystallization from methanol afforded 225 mg of crystalline titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.8 (m, 4H) 3.7 (s, 3H) 4.2 (s, 3H) 4.5(d, J 6.1 Hz, 2H) 7.2 (s, 1H) 6.8 (d, J 8.8 Hz, 2H) 7.4 (s, 1H) 7.3 (d,J 8.8 Hz, 2H) 7.6 (m, 1H) 8.2 (s, 1H)

By working according to this method, the following compounds wereprepared:

-   1-methyl-8-[(thien-3-ylmethyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B43-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.8 (m, 4H) 4.2 (s, 3H) 4.5 (d, J 6.1Hz, 2H) 7.1 (m, 1H) 7.2 (s, 1H) 7.3 (m, 1H) 7.4 (s, 1H) 7.5 (m, 1H) 7.6(m, 1H) 8.2 (s, 1H);

-   8-[(3,5-dihydroxybenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B62-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.8 (m, 4H) 4.2 (m, 2H) 4.3 (s, 3H) 4.4(d, J 6.2 Hz, 2H) 6.0 (m, 1H) 6.2 (m, 2H) 7.2 (s, 1H) 7.4 (s, 1H) 7.6(m, 1H) 8.2 (s, 1H);

-   8-({4-[3-(dimethylamino)propoxy]benzyl}amino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B61-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.8 (m, 2H) 2.2 (s, 6H) 2.4 (t, 2H) 2.8(m, 4H) 4.0 (t, 2H) 4.3 (s, 3H) 4.5 (d, J 6.5 Hz, 2H) 6.9 (m, J 9.0 Hz,2H) 7.2 (d, J 8.7 Hz, 2H) 7.2 (s, 1H) 7.4 (s, 1H) 7.6 (m, 1H) 8.2 (s,1H);

-   [5-({[3-(aminocarbonyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-8-yl]amino}methyl)-2-furyl]methyl    acetate [B65-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.0 (s, 3H) 2.8 (m, 4H) 4.3 (s, 3H) 4.5(d, J 6.1 Hz, 2H) 5.0 (s, 2H) 6.2 (d, J 3.2 Hz, 1H) 6.4 (d, J 3.2 Hz,1H) 7.2 (s, 1H) 7.4 (s, 1H) 7.6 (t, J 6.0 Hz, 1H) 8.2 (s, 1H);

-   8-[(3-cyanobenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B63-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.8 (m, 4H) 4.1 (s, 3H) 4.6 (d, J 6.1Hz, 2H) 7.2 (s, 1H) 7.4 (s, 1H) 7.5 (t, J 7.7 Hz, 1H) 7.7 (m, 4H) 8.2(s, 1H);

-   8-[(4-Bromobenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B64-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.8 (m, 4H) 4.2 (s, 3H) 4.5 (d, J 6.3Hz, 2H) 7.2 (s, 1H) 7.3 (d, J 8.5 Hz, 2H) 7.4 (s, 1H) 7.5 (d, J 8.5 Hz,2H) 7.7 (m, 1H) 8.2 (s, 1H);

-   8-{[4-(acetylamino)benzyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B80-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.0 (s, 3H) 2.7 (m, 2H) 2.9 (t, J 7.7Hz, 2H) 4.2 (s, 3H) 4.5 (d, J 6.2 Hz, 2H) 7.2 (s, 1H) 7.3 (d, J 8.5 Hz,2H) 7.4 (s, 1H) 7.5 (d, J 8.5 Hz, 2H) 7.6 (t, J 7.4 Hz, 1H) 8.2 (s, 1H)9.9 (s, 1H);

-   B81-X00-M00(C01)-D03

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.7 (m, 2H) 2.9 (t, J 7.6 Hz, 2H) 4.3(s, 3H) 4.3 (s, 2H) 4.5 (d, J 6.0 Hz, 2H) 5.1 (s, 1H) 6.2 (m, 2H) 7.2(s, 1H) 7.4 (s, 1H) 7.6 (t, J 5.9 Hz, 1H) 8.2 (s, 1H);

-   8-[(1-Methylimidazol-2-yl)methylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B82-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.8 (m, 4H) 3.7 (s, 3H) 4.3 (s, 3H) 4.6(m, 2H) 6.9 (s, 1H) 7.17 (s, 1H) 7.24 (s, 1H) 7.43 (s, 1H) 7.5 (m, 1H)8.3 (s, 1H);

-   8-[(4-Aminobenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B83-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.7 (m, 2H) 2.9 (t, J 7.7 Hz, 2H) 4.3(s, 3H) 4.4 (d, J 6.1 Hz, 2H) 5.1 (s, 2H) 6.5 (d, J 8.4 Hz, 2H) 7.0 (d,J 8.3 Hz, 2H) 7.2 (s, 1H) 7.4 (m, 2H) 8.2 (s, 1H);

-   8-[(4-Fluorobenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.73 (t, J=7.74 Hz, 2H) 2.94 (t, J=7.56Hz, 2H) 4.18 (s, 3H) 4.52 (d, J=6.22 Hz, 2H) 7.13 (t, J=8.90 Hz, 2H)7.23 (s, 1H) 7.38 (dd, J=8.66, 5.61 Hz, 2H) 7.42 (t, 1H) 7.71 (t, J=5.97Hz, 1H) 8.23 (s, 1H).

Example 488-{[4-(2-morpholinoethoxy)benzyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B84-X00-M00(C01)-D03]

Step 1.8-[(4-Hydroxybenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B85-X00-M00(C01)-D03]

To a well stirred solution of8-[(4-methoxybenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(242 mg, 0.7 mmol) in chloroform (30 mL) boron tribromide (1 M indichloromethane, 5.12 mL, 5.1 mmol) was added dropwise over a 5 minutesperiod, at room temperature. The mixture was heated to reflux for 8hours. A solution of 10% aqueous ammonium hydroxide (30 mL) was addeddropwise at 0° C. over a 10 minutes period. A precipitate was formedand, after 2 hours, it was filtered and washed with water and dried at40° C. under vacuum. There were obtained 130 mg of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.8 (m, 4H) 4.2 (s, 3H) 4.5 (m, 2H) 6.7(d, J 8.65 Hz, 2H) 7.2 (d, J 8.5 Hz, 2H) 7.25 (s, 1H) 7.4 (s, 1H) 7.8(m, 1H) 8.2 (s, 1H)

Step 2.8-{[4-(2-morpholinoethoxy)benzyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B84-X00-M00(C01)-D03]

To a solution of8-[(4-hydroxybenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(70 mg, 0.2 mmol) in anhydrous dimethylformamide (3 mL),N-morpholinoethylchloride hydrochloride (47 mg, 0.3 mmol) and powderedpotassium carbonate (45 mg, 3.3 mmol) were added. The mixture was heatedto reflux for 1 hour. The reaction mixture was poured into iced water(70 mL) and extracted with dichloromethane; the organic extracts werewashed with brine until neutral pH, then with water and dried overNa₂SO₄. The crude was purified by flash chromatography on silica gel(eluant: dichloromethane/methanol 96:4) to yield a white solid that wascrystallized from methanol, affording 47.0 mg of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.5 (m, 4H) 2.7 (t, 2H) 2.8 (m, 4H) 3.6(m, 4H) 4.0 (t, 2H) 4.2 (s, 3H) 4.5 (m, 2H) 6.9 (d, J 8.42 Hz, 2H) 7.2(s, 1H) 7.25 (d, J 8.54 Hz, 2H) 7.4 (s, 1H) 7.6 (m, 1H) 8.2 (s, 1H).

Analogously the following compound was prepared:

-   8-{[3-(2-morpholinoethoxy)-5-trifluoromethyl]phenylamino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B119-X00-M00(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.47-2.56 (m, 4H) 2.73 (t, J=7.26 Hz,2H) 2.85 (t, J=7.80 Hz, 2H) 3.01 (t, J=7.80 Hz, 2H) 3.57-3.64 (m, 4H)4.17 (t, J=5.49 Hz, 2H) 4.35 (s, 3H) 6.86 (t, J=1.83 Hz, 1H) 7.28 (s,1H) 7.48 (s, 1H) 7.61 (t, J=2.32 Hz, 1H) 7.80 (t, J=1.46 Hz, 1H) 8.49(s, 1H) 9.85 (s, 1H).

Example 492-anilino-5,6,8,9,10,11-hexahydro-7H[1,4]diazepino[l′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one[B04-X00-M06]

Step 1. Ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

1 g (4.2 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetatewere dissolved in 10 mL of ethanol, 0.21 mL of hydrazine hydrate wereadded and the solution stirred at reflux for a day. The solvent was thenevaporated and the residue redissolved with dichloromethane. The organiclayer was washed with water, dried over Na₂SO₄ and concentrated. Thecrude was triturated with diethyl ether and filtered to give (70% yield)the title compound.

1H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (t, J 6.83 Hz 3H) 2.25-3-27 (3m,6H) 4.18 (q, J 6.83 Hz, 2H) 8.45 (bs, 1H).

Analogously the following compound was prepared:

-   Ethyl    4,4-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=6.95 Hz, 3H) 1.42 (s, 6H)1.90-2.02 (m, 2H) 2.55-2.63 (m, 2H) 4.33 (q, J=6.95 Hz, 2H) 14.34 (s,1H).

Step 2. Ethyl 7-oxo-1(and2)-trityl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

1.20 g (4.8 mmol) of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 40mL of dichloromethane and 0.76 mL of triethylamine and 1.47 g (5.3 mmol)of triphenylmethyl chloride were added. The solution was stirred at roomtemperature for 6 hours. Then the solution was diluted with furtherdichloromethane and washed with water. The organic layer was treatedwith anhydrous Na₂SO₄ and evaporated to dryness. The product, as amixture of regioisomers, was finally obtained by crystallization fromdiethyl ether (80% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (t, 3H) 1.94-2.98 (3m, 6H) 4.25 (q,2H) 6.85-7.36 (2m, 15H).

Analogously the following compounds were prepared:

-   Ethyl    1-trityl-4,4-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.26 (t, J=7.07 Hz, 3H) 1.45 (s, 6H)1.79-1.88 (m, 2H) 2.18-2.26 (m, 2H) 4.27 (q, J=7.15 Hz, 2H) 6.84-7.01(m, 6H) 7.14-7.33 (m, 9H);

-   Ethyl    2-trityl-4,4-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88 (t, J=7.13 Hz, 3H) 1.27 (s, 6H)1.92-1.99 (m, 2H) 2.56-2.63 (m, 2H) 3.44 (q, J=7.15 Hz, 2H) 6.99-7.05(m, 6H) 7.31-7.37 (m, 9H).

Step 3.Ethyl-6-[(dimethylamino)methylene]-7-oxo-1(2)-trityl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

3.0 g (6.6 mmol) of ethyl7-oxo-1(2)-trityl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate weredissolved in 20 mL of dimethylformamide and 3.2 mL (13.2 mmol) ofdimethylformamide ditertbutylacetale were added. The solution was heatedat 65° C. under stirring for a day and then evaporated to dryness. Theproduct was obtained by crystallization from a mixture diethylether/ethyl acetate (90% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 and 0.79 (2t, J 7.07 Hz, 3H)2.70-2.90 (2t, J 6.71 Hz, 6H) 2.94 and 2.99 (2m, 6H) 4.21 (q, J 7.07 Hz,2H) 6.90-7.30 (m, 15H).

Analogously the following compounds were prepared:

-   Ethyl    6-[(dimethylamino)methylene]-1-trityl-4,4-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (t, J=7.13 Hz, 3H) 1.36 (s, 6H)2.66 (s, 2H) 2.98 (s, 6H) 4.25 (q, 0.1=7.15 Hz, 2H) 6.96 (t, 7H)7.15-7.29 (m, 9H);

-   Ethyl    6-[(dimethylamino)methylene]-2-trityl-4,4-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90 (t, J=7.19 Hz, 3H) 1.19 (s, 6H)2.78 (s, 2H) 3.11 (s, 6H) 3.42 (q, J=7.23 Hz, 2H) 6.97-7.09 (m, 6H)7.30-7.37 (m, 9H) 7.48 (s, 1H).

Step 4. Ethyl 8-anilino-1(and2)-trityl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

To a solution of 636 mg of ethyl6-[(dimethylamino)methylene]-7-oxo-1(2)-trityl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate(1.18 mmol) and 440 mg (1.18 mmol) of phenylguanidine carbonate in 100mL of absolute ethanol, 0.5 mL of diazabicycloundecene were added. Themixture was stirred at reflux for 48 hours and then the solventevaporated under reduced pressure. The residue was redissolved withdichloromethane and washed with water. The organic layer was dried overNa₂SO₄ and purified by chromatography on a silica gel column (eluantcyclohexane/ethyl acetate 8/2) to give 240 mg of the title compound (35%yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (t, J 7.20 Hz, 3H) 2.80-2.95 (m,4H) 3.58 (q, J 7.20 Hz, 2H) 6.85-7.80 (5m, 20H) 8.38 (bs, 1H) 9.49 (bs,1H).

According to the same method but employing the suitable guanidinederivatives, the following compounds were prepared:

-   Ethyl    8-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-1(and    2)-trityl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl 8-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-1(and    2)-trityl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl 8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1 (and    2)-trityl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl 8-amino-1 (and    2)-trityl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl 8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1-trityl-4,4    dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (t, J 7.20 Hz, 3H) 1.31 (s, 6H)2.20 (s, 3H) 2.43 (m, 4H) 2.56 (m, 2H) 2.99 (m, 4H) 4.24 (q, J 7.20 Hz,2H) 6.61 (d, J=8.79 Hz, 2H) 6.92-7.37 (m, 17H) 8.07 (bs, 1H);

-   Ethyl 8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-2-trityl-4,4    dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (t, J 7.20 Hz, 3H) 1.17 (s, 6H)2.21 (s, 3H) 2.46 (m, 4H) 2.71 (m, 2H) 3.04 (m, 4H) 3.40 (q, J 7.20 Hz,2H) 6.80 (d, J=8.79 Hz, 2H) 6.96-7.43 (m, 15H) 7.60 (d, J=8.79 Hz, 2H)8.31 (bs, 1H) 9.31 (bs, 1H);

-   Ethyl 8-anilino-1 (and 2)-trityl-4,4    dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   Ethyl    8-amino-1-trityl-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (t, J=7.13 Hz, 3H) 1.31 (s, 6H)2.52 (s, 2H) 4.27 (q, J=7.07 Hz, 2H) 5.20 (s, 2H) 7.03-7.09 (m, 6H)7.16-7.34 (m, 9H) 7.93 (s, 1H);

-   Ethyl    8-amino-2-trityl-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (t, J=7.13 Hz, 3H) 1.16 (s, 6H)2.63 (s, 2H) 3.46 (q, J=7.07 Hz, 2H) 6.47 (s, 2H) 7.09-7.16 (m, 6H)7.24-7.41 (m, 9H) 8.14 (s, 1H).

Step 5. Ethyl8-anilino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate

-   [B04-X00-M00(C00)-D01]

1.50 g (2.6 mmol) of ethyl8-anilino-1(2)-trityl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatewere dissolved in 50 mL of dichloromethane and 5 mL of trifluoroaceticacid were added. The solution was stirred overnight and the solventremoved in vacuo. The residue was redissolved in dichloromethane andwashed with a saturated solution of NaHCO₃. The organic layer was thendried over Na₂SO₄ and the solvent evaporated to dryness. Bycrystallization from diisopropyl ether 0.70 mg of the title compoundwere obtained (80% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (t, 3H, J 7.07 Hz) 3.05-3.28 (2m,4H) 4.18 (q, 2H, J 7.07 Hz) 6.83-7.63 (3m, 5H) 8.31 (bs, 1H) 9.10 (m,2H).

According to the same method the following compounds were prepared:

-   Ethyl    8-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B12-X00-M00(C00)-D01]-   Ethyl    8-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B13-X00-M00(C00)-D01]-   Ethyl    8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B10-X00-M00(C00)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (t, J 7.20 Hz, 3H) 2.30 (s, 3H)2.50-2.60 (m, 4H) 2.86 (m, 2H) 2.99 (m, 2H) 3.10 (m, 4H) 4.33 (q, J 7.20Hz, 2H) 6.90 (d, J=8.90 Hz, 2H) 7.71 (d, J=8.90 Hz, 2H) 8.34 (s, 1H)9.27 (bs, 1H) 14.22 (bs, 1H)

-   Ethyl    8-amino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B00-X00-M00(C00)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, 3H, J 7.2 Hz) 2.78 (m, 2H) 2.96(m, 2H) 4.31 (q, 2H, J 7.2 Hz) 6.64 (m, 2H) 8.19 (bs, 1H);

-   Ethyl    8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B10-X00-M03(C00)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (t, J 7.20 Hz, 3H) 1.33 (s, 6H)2.22 (s, 3H) 2.40-2.50 (m, 4H) 2.73 (m, 2H) 3.07 (m, 4H) 4.35 (q, J 7.20Hz, 2H) 6.91 (d, J=9.02 Hz, 2H) 7.70 (d, J=9.02 Hz, 2H) 8.33 (bs, 1H)9.30 (bs, 1H) 14.13 (bs, 1H);

-   Ethyl    8-amino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B00-X00-M03(C00)-D01]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (m, 9H) 2.66 (s, 2H) 4.22-4.42 (m,2H) 6.36 (d, 2H) 8.19 (d, 1H) 14.11 (d, 1H);

-   Ethyl    8-anilino-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    [B04-X00-M03(C00)-D01].

Step 6. Ethyl8-anilino-2-{3-[(tert-butoxycarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate

500 mg of ethyl8-anilino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.5mmol) were dissolved in 10 mL of dry dimethylformamide and 1.63 mL of 1M lithium tert-butoxide in tetrahydrofuran were added to the cooledsolution. After 30 minutes under stirring at 0° C. a solution of 432 mgof tert-butoxycarbonylaminopropyl bromide in 8 mL of dry tetrahydrofuranwere added dropwise. After a night at room temperature the mixture waspoured into a solution of NaH₂PO₄ and extracted with dichloromethane.The organic layer was then dried over Na₂SO₄ and the solvent evaporated,giving an oil that was treated according to the following step 7,without any further purification.

Analogously the following compounds can be prepared:

-   Ethyl    2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl    2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl    2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl    8-amino-2-{3-[(tert-butoxycarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   Ethyl    8-amino-2-{3-[(tert-butoxycarbonyl)amino]propyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   Ethyl    8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-2-{3-[(tert-butoxycarbonyl)amino]propyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   Ethyl    8-anilino-2-{3-[(tert-butoxycarbonyl)amino]propyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate.

Following the above method, but employing tert-butoxycarbonylaminoethylbromide, the following compounds were prepared:

-   Ethyl    8-anilino-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   Ethyl    2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl    2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl    2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate-   Ethyl    8-amino-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (s, 9H) 1.36 (t, 3H, J 7.2 Hz) 2.74(m, 2H) 2.94 (m, 2H) 3.34 (m, 2H) 4.33 (q, 2H, J 7.2 Hz) 4.57 (t, 2H)6.50 (m, 2H) 6.87 (t, 1H) 8.15 (bs, 1H);

-   Ethyl    8-amino-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,4-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   Ethyl    8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate;-   Ethyl    8-anilino-2-{2-[(tert-butoxycarbony)amino]ethyl}-4,4-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate.

Step 7. Ethyl2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylatehydrochloride [B04-X00-M04(C13)-D01]

The crude of previous step 6 was dissolved in 20 mL of dioxane and 8 mLof HCl 37% were added. After 6 hours under stirring at room temperaturethe solvent was removed in vacuo, the residue triturated with ethanoland the product collected by filtration (80% yield).

By working according to the above method, the following compounds wereprepared:

-   B04-X00-M04(C12)-D01-   B00-X00-M04(C12)-D01

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (t, 3H, J 7.2 Hz) 2.85 (m, 2H) 3.02(m, 2H) 3.50 (m, 2H) 4.37 (q. 2H, J 7.2 Hz) 4.84 (t, 2H) 7.47 (m, 1H)8.08 (m, 3H) 8.29 (s, 1H);

-   B12-X00-M04(C12)-D01-   B13-X00-M04(C12)-D01-   B10-X00-M04(C12)-D01-   B12-X00-M04(C13)-D01-   B13-X00-M04(C13)-D01-   B10-X00-M04(C13)-D01-   Ethyl    8-amino-2-(3-aminopropyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    hydrochloride B00-X00-M04(C13)-D01;-   Ethyl    8-amino-2-(3-aminopropyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    hydrochloride B00-X00-M09(C13)-D01;-   Ethyl    2-(3-aminopropyl)-8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    hydrochloride B10-X00-M09(C13)-D01;-   Ethyl    8-anilino-2-(3-aminopropyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    hydrochloride B04-X00-M09(C13)-D01;-   Ethyl    8-amino-2-(3-aminoethyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    hydrochloride B00-X00-M09(C12)-D01;-   Ethyl    2-(3-aminoethyl)-8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    hydrochloride B10-X00-M09(C12)-D01;-   Ethyl    8-anilino-2-(3-aminoethyl)-4,4-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate    hydrochloride B04-X00-M09(C12)-D01.

Step 8.2-anilino-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one[B04-X00-M06]

185 mg (0.43 mmol) of ethyl2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylatehydrochloride were dissolved in 10 mL of methanol and 400 mg of cesiumcarbonate were added. After 3 hours under stirring at room temperaturethe solvent was removed at reduced pressure. Water was then added to theresidue and the solid collected by filtration and washed with water andacetone to give 100 mg (70% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.18 (ddd, J 13.02, 6.65, 6.55 Hz, 2H)2.88 (m, 4H) 3.21 (q, J 5.89 Hz, 2H) 4.50 (t, J 6.77 Hz, 2H) 6.93 (t, J7.32 Hz, 1H) 7.28 (dd, J 8.29, 7.56 Hz, 2H) 7.85 (d, J 7.68 Hz, 2H) 8.27(t, J 5.18 Hz, 1H) 8.38 (s, 1H) 9.62 (s, 1H)

By working according to this method the following compounds wereprepared:

-   2-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B04-X00-M05]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.92 (m, 4H) 3.65 (m, 2H) 4.41 (m, 2H)6.93 (m, 1H) 7.28 (m, 2H) 7.85 (m, 2H) 8.26 (m, 1H) 8.39 (s, 1H) 9.61(s, 1H);

-   2-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B12-X00-M05]-   2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B13-X00-M05]-   2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B10-X00-M05]-   2-amino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B00-X00-M05]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74 (t, J=7.56 Hz, 2H) 2.88-2.98 (m,2H) 3.60-3.68 (m, 2H) 4.29-4.42 (m, 2H) 6.48 (s, 2H) 8.15 (s, 1H)8.21-8.32 (m, 1H);

-   2-amino-5,6,8,9,10,11-hexahydro-7H[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one    [B00-X00-M06]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.18 (ddd, J 13.02, 6.65, 6.55 Hz, 2H)2.74 (m, 2H) 2.92 (m, 2H) 3.21 (q, J 5.89 Hz, 2H) 4.50 (t, J 6.77 Hz,2H) 6.48 (m, 2H) 8.17 (s, 1H) 8.23 (m, 1H);

-   2-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one[B12-X00-M06]-   2-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5,6,8,9,10,11-hexahydro-7H[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one    [B13-X00-M06]-   2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,6,8,9,10,11-hexahydro-7H[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one    [B10-X00-M06]-   2-amino-6,6-dimethyl-5,9,10-trihydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B00-X00-M07];-   2-anilino-6,6-dimethyl-5,9,10-trihydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B04-X00-M07];-   2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-6,6-dimethyl-5,9,10-trihydropyrazino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7(8H)-one    [B10-X00-M07]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 6H) 2.23 (s, 3H) 2.47 (m, 4H)2.92 (m, 2H) 3.07 (m, 4H) 3.65 (m, 2H) 4.41 (m, 2H) 6.91 (d, J=9.02 Hz,2H) 7.53 (d, J=9.02 Hz, 2H) 8.23 (m, 1H) 8.34 (s, 1H) 9.12 (s, 1H);

-   2-amino-6,6-dimethyl-5,8,9,10,11-pentahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one    [B00-X00-M08];-   2-anilino-6,6-dimethyl-5,8,9,10,11-pentahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one    [B04-X00-M08];-   2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-6,6-dimethyl-5,8,9,10,11-pentahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one    [B10-X00-M08]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 6H) 2.18 (ddd, J 13.02, 6.65,6.55 Hz, 2H) 2.23 (s, 3H) 2.47 (m, 4H) 2.92 (m, 2H) 3.07 (m, 4H) 3.21(q, J 5.89 Hz, 2H) 4.50 (t, J 6.77 Hz, 2H) 6.91 (d, J=9.02 Hz, 2H) 7.53(d, J=9.02 Hz, 2H) 8.27 (m, 1H) 8.34 (s, 1H) 9.12 (s, 1H).

Example 508-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid [B04-X00-M00(C01)-D02]

0.63 g (1.80 mmol) of ethyl8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylatewere dissolved in 100 mL of a mixture tetrahydrofuran/methanol/water8/1/1 and 0.19 g (4.53 mmol) of lithium hydroxide hydrate were added.The solution was stirred at 60° C. for 1.5 hours. The mixture was thencooled to room temperature and 1 N HCl added until neutral pH. Water wasadded and the resulting precipitate collected by filtration (87% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85 (t, J 7.74 Hz, 2H) 2.99 (m, 2H)4.36 (s, 3H) 6.98 (tt, J 7.35, 1.07 Hz, 1H) 7.31 (dd, J 8.47, 7.50 Hz,2H) 7.72 (dd, J 8.60, 0.91 Hz, 2H) 8.42 (s, 1H) 9.52 (s, 1H) 12.68 (s,1H)

By working according to the same procedure the following compounds wereprepared:

-   B00-X00-M00(C01)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.48 and 3.64 (2t, J 7.25 Hz, 4H) 3.84(s, 3H) 8.04 (bs, 2H) 8.46 (bs, 1H);

-   B09-X00-M00(C03)-D02

¹H NMR (400 MHz, DMSO-d₆ Hz) 6.49 (m, 1H) 7.07 (m, 2H) 7.94 (bs, 1H)8.30 (s, 1H) 9.35 (bs, 1H);

-   B09-X00-M04(C03)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (s, 9H) 1.62 (m, 2H) 2.26 (s, 3H)2.52 (m, 4H) 3.13 (m, 4H) 4.86 (m, 2H) 6.58 (m, 1H) 7.13 (m, 1H) 7.20(m, 1H) 8.41 (s, 1H) 9.20 (bs, 1H);

-   B10-X00-M00(C01)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.89 (s, 3H) 2.74 (m, 2H) 2.95 (m, 2H)4.30 (s, 3H) 6.93 (m, 2H) 7.52 (m, 2H) 8.33 (s, 1H) 9.28 (bs, 1H);

-   B103-X00-M00(C01)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.09 (m, 4H) 2.83 (m, 5H) 2.97 (t, 2H)4.33 (s, 3H) 7.02 (m, 2H) 7.61 (m, 2H) 8.38 (s, 1H) 9.39 (s, 1H);

-   B09-X00-M00(C01)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.81 (m, 5H) 2.93 (t, 2H) 3.09 (m, 4H)3.71 (m, 4H) 4.32 (s, 3H) 6.64 (m, 1H) 7.17 (m, 1H) 7.29 (m, 2H) 8.38(s, 1H) 9.42 (s, 1H) 10.33 (s, 1H);

-   B04-X04-M00(C01)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.89 (t, 2H) 2.97 (t, 2H) 3.70 (s, 3H)7.51 (m, 3H) 7.67 (m, 2H) 8.56 (s, 1H) 12.81 (bs, 1H);

-   B05-X06-M00(C01)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.92 (t, 2H) 2.97 (t, 2H) 4.23 (s, 2H)4.26 (s, 3H) 7.23 (m, 1H) 7.32 (m, 2H) 7.36 (m, 2H) 8.65 (s, 1H) 12.82(bs, 1H);

-   B10-X00-M04(C15)-D02

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.60 (m, 5H) 2.89 (m, 2H) 3.04 (m, 4H)3.33 (m, 4H) 6.31 (s, 2H) 6.78 (d, 2H) 7.39 (m, 3H) 7.47 (m, 2H) 7.63(m, 2H) 7.67 (s, 1H) 8.42 (s, 1H) 9.33 (s, 1H) 13.55 (s, 1H).

Example 518-anilino-1-methyl-N-phenyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B04-X00-M00(C01)-D20]

45 mg (0.14 mmol) of8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid were dissolved in 7 mL of dimethylformamide and 145.6 mg (0.28mmol) of (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP); 0.12 mL (0.70 mmol) ofN,N-diisopropyl-N-ethyl amine and 0.08 mL (0.70 mmol) of aniline werethen added. After 6 hours the solvent was removed, the residue wasredissolved with dichloromethane and washed with water. The organiclayer was dried over Na₂SO₄ and evaporated to dryness. The productcrystallized from methanol (60% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.88 (m, 2H) 3.07 (m, 2H) 4.43 (s, 3H)6.97-7.85 (6m, 10H) 8.45 (s, 1H) 9.55 (s, 1H) 10.09 (s, 1H).

By working analogously the following compounds were prepared:

TABLE XIII B04-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.72 (d,J = 4.76 Hz, 3 H) 2.79 (t, J = 7.68 Hz, 2 H) 2.97 (t, J = 7.68 Hz, 2 H)4.31 (s, 3 H) 6.94 (t, J = 7.38 Hz, 1 H) 7.21-7.32 (m, 2 H) 7.68 (d, J =7.56 Hz, 2 H) 8.06 (q, J = 4.35 Hz, 1 H) 8.38 (s, 1 H) 9.48 (s, 1 H)B04-X00-M00(C01)-D08 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.89 (m, 4 H) 2.83(m, 2 H) 2.94 (m, 2 H) 3.49 (t, J 6.77 Hz, 2 H) 3.83 (t, J 6.58 Hz, 2 H)4.34 (s, 3 H) 6.97 (t, J 7.32 Hz, 1 H) 7.31 (dd, J 8.29, 7.56 Hz, 2 H)7.73 (d, J 7.44 Hz, 2 H) 8.42 (s, 1 H) 9.51 (s, 1 H)B04-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.65 (m, 2 H) 3.01(m, 2 H) 4.36 (s, 3 H) 4.43 (d, J 6.34 Hz, 2 H) 6.97 (t, J 7.32 Hz, 1 H)7.31 (m, 7 H) 7.72 (d, J 7.5 Hz, 2 H) 8.42 (s, 1 H) 8.71 (t, J 6.4 Hz, 1H) 9.52 (s, 1 H) B04-X00-M00(C01)-D10 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.65-3.5 (m, 15 H) 4.35 (s, 3 H) 6.98 (t, J 7.4 Hz, 1 H) 7.32 (dd, J8.29, 7.56 Hz, 2 H) H) 7.73 (d, J 7.5 Hz, 2 H) 8.44 (s, 1 H) 9.55 (s, 1H) B04-X00-M00(C01)-D11 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88 (d, J 6.71Hz, 6 H) 1.86 (m, 1 H) 2.83 (dd, J 8.05, 7.19 Hz, 2 H) 3.00 (t, J 7.74Hz, 2 H) 3.07 (t, J 6.58 Hz, 2 H) 4.36 (s, 3 H) 6.97 (tt, J 7.32, 1.10Hz, 1 H) 7.31 (dd, J 8.47, 7.50 Hz, 2 H) 7.72 (dd, J 8.54, 0.98 Hz, 2 H)8.09 (t, J 6.16 Hz, 1 H) 8.42 (s, 1 H) 9.52 (s, 1 H)B04-X00-M00(C01)-D12 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.83 (m, 2 H) 3.01(m, 2 H) 3.28 (s, 3 H) 3.43 (m, 4 H) 4.36 (s, 3 H) 6.98 (m, 1 H) 7.31(dd, J 8.41, 7.44 Hz, 2 H) 7.72 (dd, J 8.66, 0.98 Hz, 2 H) 7.99 (t, J5.49 Hz, 1 H) 8.42 (s, 1 H) 9.52 (s, 1 H) B04-X00-M00(C01)-D13 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.16 (m, 6 H) 1.83 (m, 2 H) 2.83 (m, 2 H) 3.01(m, 2 H) 2.9-3.5 (m, 8 H) 4.36 (s, 3 H) 6.97 (m, 1 H) 7.31 (m, 2 H) 7.72(dd, J 8.54, 0.98 Hz, 2 H) 8.09 (t, J 6.16 Hz, 1 H) 8.43 (s, 1 H) 9.53(s, 1 H) B04-X00-M00(C01)-D14 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (m, 4H) 1.70 (m, 2 H) 1.85 (m, 2 H) 2.83 (m, 2 H) 3.0 (m, 2 H) 4.21 (m, 1 H)4.35 (s, 3 H) 6.97 (t, J 7.32 Hz, 1 H) 7.31 (dd, J 8.29, 7.56 Hz, 2 H)7.73 (d, J 7.44 Hz, 2 H) 8.42 (s, 1 H) 9.51 (s, 1 H)B04-X00-M00(C01)-D15 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.65 (s, 3 H) 2.83(m, 2 H) 3.01 (m, 2 H) 3.06 (m, 8 H) 4.42 (s, 3 H) 6.75 (m, 1 H) 6.99(t, J 7.32 Hz, 1 H) 7.20 (t, J 8.05 Hz, 1 H) 7.32 (m, 3 H) 7.55 (bs, 1H) 7.72 (dd, J 8.66, 0.98 Hz, 2 H) 8.45 (s, 1 H) 9.55 (s, 1 H) 9.91 (s,1 H) B04-X00-M00(C01)-D16 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84 (m, 2 H)3.01 (m, 2 H) 4.35 (s, 3 H) 4.43 (d, J 6.10 Hz, 2 H) 6.25 (dd, J 3.17,0.85 Hz, 1 H) 6.40 (dd, J 3.17, 1.83 Hz, 1 H) 6.97 (m, 1 H) 7.31 (dd, J8.54, 7.44 Hz, 2 H) 7.57 (dd, J 1.83, 0.85 Hz, 1 H) 7.72 (dd, J 8.60,1.04 Hz, 2 H) 8.42 (s, 1 H) 8.54 (t, J 6.04 Hz, 1 H) 9.52 (s, 1 H)B04-X00-M00(C01)-D17 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.7 (m, 2 H) 2.83(m, 2 H) 3.01 (m, 2 H) 3.2-3.7 (m, 12 H) 4.35 (s, 3 H) 6.98 (m, 1 H)7.32 (dd, J 8.54, 7.44 Hz, 2 H) 7.72 (dd, J 8.54, 0.98 Hz, 2 H) 8.38 (m,1 H) 8.42 (s, 1 H) 9.52 (s, 1 H) B00-X00-M00(C21)-D04] ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.94 (d, J = 10.73 Hz, 2 H) 2.11-2.31 (m, 4 H) 2.70 (t, J= 7.93 Hz, 2 H) 2.76 (d, J = 4.76 Hz, 3 H) 2.86-3.02 (m, J = 7.56, 7.56Hz, 4 H) 3.55 (s, 2 H) 5.50-5.62 (m, 1 H) 6.51 (s, 2 H) 7.19-7.39 (m, 5H) 7.93-8.04 (m, 1 H) 8.17 (s, 1 H) B00-X00-M00(C01)-D18 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.79 (m, 2 H) 3.03 (m, 2 H) 4.40 (s, 3 H) 6.61 (bs,2 H) 7.18 (m, 1 H) 7.87 (m, 1 H) 8.18 (m, 1 H) 8.22 (m, 1 H) 8.37 (m, 1H) 9.46 (s, 1 H). B04-X00-M00(C01)-D27 B04-X00-M04(C01)-D27B04-X00-M00(C21)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.93 (d, J = 9.76Hz, 2 H) 2.00-2.10 (m, 2 H) 2.13-2.28 (m, 2 H) 2.81 (t, J = 7.44 Hz, 2H) 2.88 (d, J = 11.22 Hz, 2 H) 3.00 (t, J = 7.62 Hz, 2 H) 3.51 (s, 2 H)4.42-4.50 (m, J = 6.46 Hz, 2 H) 5.49-5.62 (m, 1 H) 6.99-7.40 (m, 13 H)7.61 (d, J = 8.66 Hz, 2 H) 8.42 (s, 1 H) 8.68 (t, J = 6.16 Hz, 1 H) 9.44(s, 1 H) B04-X00-M00(C01)-D19 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85 (m, 4H) 3.01 (m, 2 H) 3.49 (m, 2 H) 4.35 (s, 3 H) 6.97 (m, 1 H) 7.31 (m, 7 H)7.72 (dd, J 8.60, 1.04 Hz, 2 H) 8.18 (m, 1 H) 8.42 (s, 1 H) 9.52 (s, 1H) B10-X00-M00(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.75 (d, J =4.76 Hz, 3 H) 2.81 (t, J = 7.68 Hz, 2 H) 2.85 (d, J = 4.39 Hz, 3 H)2.94-3.07 (m, 4 H) 3.11-3.25 (m, 2 H) 3.51 (d, J = 11.83 Hz, 2 H) 3.73(d, J = 13.66 Hz, 2 H) 4.33 (s, 3 H) 6.99 (d, J = 9.15 Hz, 2 H) 7.60 (d,J = 9.02 Hz, 2 H) 8.08 (q, J = 4.67 Hz, 1 H) 8.37 (s, 1 H) 9.40 (s, 1 H)10.36 (s, 1 H) B10-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29(s, 3 H) 2.55 (m, 4 H) 2.80 (m, 2 H) 2.99 (m, 2 H) 3.10 (m, 2 H) 4.34(s, 3 H) 4.44 (d, J 6.34 Hz, 2 H) 6.92 (d, J 9.02 Hz, 2 H) 7.25 (m, 1 H)7.32 (m, 4 H) 7.72 (d, J 7.5 Hz, 2 H) 8.35 (s, 1 H) 8.69 (t, J 6.4 Hz, 1H) 9.26 (s, 1 H) B10-X00-M00(C01)-D21 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.27 (s, 3 H), 2.80 (t, 2 H), 2.99 (t, 2 H), 3.09 (bs, 4 H), 3.34 (m, 4H), 4.34 (s, 3 H), 4.40 (d, 2 H), 6.93 (d, 2 H), 7.15 (t, 2 H), 7.37 (t,2 H), 7.53 (d, 2 H), 8.35 (s, 1 H), 8.74 (t, 1 H), 9.26 (s, 1 H).B10-X00-M00(C01)-D22 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H), 2.80(t, 2 H), 2.99 (t, 2 H), 3.09 (bs, 4 H), 3.34 (m, 4 H), 3.74, (s, 3 H),4.33 (d + s, 5 H), 6.90 (t, 4 H), 7.25 (d, 2 H), 7.53 (d, 2 H), 8.35 (s,1 H), 8.60 (t, 1 H), 9.26 (s, 1 H). B10-X00-M00(C01)-D23 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H), 2.52 (m, 4 H), 2.80 (t, 2 H), 2.99(t, 2 H), 3.09 (bs, 4 H), 4.35 (s, 3 H), 4.50 (d, 2 H), 6.93 (d, 2 H),7.55 (m, 4 H), 7.69 (d, 2 H), 8.35 (s, 1 H), 8.87 (t, 1 H), 9.26 (s, 1H). B10-X00-M00(C01)-D24 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50 (d, 3 H),2.24 (s, 3 H), 2.47 (m, 4 H), 2.78 (t, 2 H), 2.96 (t, 2 H), 3.08 (m, 4H), 4.35 (s, 3 H), 5.15 (m, 1 H), 6.91 (d, 2 H), 7.24 (m, 1 H), 7.33 (t,2 H), 7.42 (m, 2 H), 7.53 (d, 2 H), 8.34 (s, 1 H), 8.43 (d, 1 H), 9.25(s, 1 H). B10-X00-M00(C19)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (s,3 H) 2.24 (s, 3 H) 2.48 (m, 4 H) 3.12 (m, 4 H) 5.44 (m, 1 H) 6.95 (m, 2H) 7.38 (m, 2 H) 7.94 (s, 1 H) 8.34 (s, 1 H) 9.12 (s, 1 H).B10-X00-M00(C01)-D40 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.80(t, 2 H) 2.99 (t, 3 H) 3.09 (m, 4 H) 4.35 (s, 3 H) 4.43 (d, 2 H) 6.93(d, 2 H) 7.07 (m, 1 H) 7.14 (m, 1 H) 7.18 (m, 1 H) 7.37 (m, 1 H) 7.53(d, 2 H) 8.35 (m, 1 H) 8.79 (t, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D16¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.95 (m, 15 H) 4.33 (s, 3 H) 4.43 (d, J= 5.97 Hz, 2 H) 6.25 (dd, J = 3.17, 0.85 Hz, 1 H) 6.40 (dd, J = 3.23,1.89 Hz, 1 H) 6.94 (d, J = 9.02 Hz, 2 H) 7.56 (d, J = 9.02 Hz, 2 H) 7.57(dd, J = 1.83, 0.85 Hz, 1 H) 8.36 (s, 1 H) 8.52 (t, J = 6.16 Hz, 1 H)9.29 (s, 1 H) B10-X00-M00(C01)-D76 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26(s, 3 H) 2.52 (m, 12 H) 2.80 (t, 2 H) 2.99 (t, 2 H) 3.08 (m, 4 H) 3.59(m, 4 H) 4.33 (s, 3 H) 6.92 (d, 2 H) 7.52 (d, 2 H) 7.99 (t, 1 H) 8.35(s, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D47 ¹H NMR (400 MHz, DMSO-d₆) δppm 2.36 (s, 3 H) 2.64 (m, 4 H) 2.78 (t, 2 H) 2.96 (t, 2 H) 3.13 (m, 4H) 4.35 (s, 3 H) 5.15 (m, 1 H) 6.94 (d, 2 H) 7.24 (m, 1 H) 7.33 (m, 2 H)7.41 (m, 2 H) 7.54 (d, 2 H) 8.34 (s, 1 H) 8.42 (d, 1 H) 9.27 (s, 1 H)B10-X00-M00(C01)-D61 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49 (d, 3 H) 2.27(s, 3 H) 2.78 (t, 2 H) 2.96 (t, 2 H) 3.09 (m, 4 H) 4.35 (s, 3 H) 5.15(m, 1 H) 6.93 (d, 2 H) 7.24 (m, 1 H) 7.33 (m, 2 H) 7.41 (m, 2 H) 7.52(d, 2 H) 8.34 (s, 1 H) 8.42 (d, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D50¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3 H) 2.52 (m, 4 H) 2.80 (t, 2H) 2.99 (t, 2 H) 3.08 (m, 4 H) 3.60 (s, 3 H) 4.32 (s, 3 H) 4.39 (d, 2 H)5.89 (m, 1 H) 5.97 (m, 1 H) 6.64 (m, 1 H) 6.92 (d, 2 H) 7.52 (d, 2 H)8.26 (t, 1 H) 8.35 (s, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D44 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.49 (m, 4 H) 2.82 (t, 2 H) 3.01(t, 2 H) 3.10 (m, 4 H) 4.38 (s, 3 H) 4.46 (d, 2 H) 6.94 (d, 2 H) 7.33(d, 2 H) 7.55 (d, 2 H) 8.37 (s, 1 H) 8.52 (d, 2 H) 8.88 (t, 1 H) 9.29(s, 1 H) B10-X00-M00(C01)-D45 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3H) 2.80 (t, 2 H) 2.99 (t, 2 H) 3.09 (m, 4 H) 4.34 (s, 3 H) 4.44 (d, 2 H)6.93 (d, 2 H) 7.38 (m, 1 H) 7.53 (d, 2 H) 7.72 (m, 1 H) 8.35 (s, 1 H)8.46 (m, 1 H) 8.55 (m, 1 H) 8.83 (t, 1 H) 9.26 (s, 1 H)B10-X00-M00(C01)-D34 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28 (m, 3 H) 2.53(m, 4 H) 2.78 (m, 2 H) 2.94 (m, 2 H) 3.10 (m, 4 H) 3.74 (m, 2 H) 4.37(m, 3 H) 5.00 (t, 1 H) 5.03 (m, 1 H) 6.92 (m, 2 H) 7.25 (m, 1 H) 7.33(m, 2 H) 7.39 (m, 2 H) 7.54 (m, 2 H) 8.27 (d, 1 H) 8.34 (m, 1 H) 9.26(m, 1 H) B10-X00-M00(C01)-D60 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3H) 2.52 (m, 4 H) 2.78 (t, J = 7.74 Hz, 2 H) 2.95 (t, 2 H) 3.09 (m, 4 H)3.74 (m, 2 H) 4.37 (s, 3 H) 5.01 (m, 2 H) 6.92 (d, 2 H) 7.30 (m, 5 H)7.53 (d, 2 H) 8.27 (d, J = 8.29 Hz, 1 H) 8.34 (s, 1 H) 9.26 (s, 1 H)B10-X00-M00(C01)-D42 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.52(m, 4 H) 2.80 (t, 2 H) 2.99 (s, 2 H) 3.09 (m, 4 H) 4.34 (s, 3 H) 4.39(d, 2 H) 6.93 (d, 2 H) 7.18 (m, 1 H) 7.37 (m, 2 H) 7.53 (d, 2 H) 8.35(s, 1 H) 8.81 (t, 1 H) 9.26 (m, 1 H) B10-X00-M00(C01)-D41 ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.89 (t, J = 7.32 Hz, 3 H) 1.87 (m, 2 H) 2.27 (s, 3H) 2.52 (m, 4 H) 2.77 (m, 2 H) 2.95 (m, 2 H) 3.09 (m, 4 H) 4.35 (s, 3 H)4.88 (td, J = 8.75, 6.40 Hz, 1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.23 (m, 1H) 7.33 (t, J = 7.50 Hz, 2 H) 7.42 (m, 2 H) 7.54 (d, J = 9.02 Hz, 2 H)8.34 (s, 1 H) 8.41 (d, J = 8.78 Hz, 2 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D54 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.24 (s, 3 H) 2.52(m, 10 H) 2.78 (t, 2 H) 2.95 (m, 4 H) 3.08 (m, 4 H) 3.59 (m, 4 H) 4.37(s, 3 H) 5.16 (m, 1 H) 6.92 (d, 2 H) 7.24 (m, 1 H) 7.33 (m, 2 H) 7.42(m, 2 H) 7.53 (d, 2 H) 8.34 (s, 1 H) 8.40 (d, 1 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D67 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (s, 3 H) 2.26(s, 3 H) 2.51 (m, 4 H) 2.80 (t, J = 7.68 Hz, 2 H) 2.99 (t, J = 7.68 Hz,2 H) 3.08 (m, 4 H) 3.66 (s, 3 H) 4.30 (d, J = 5.97 Hz, 2 H) 4.32 (s, 3H) 5.94 (s, 1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.54 (d, J = 9.02 Hz, 2 H)8.23 (t, J = 5.97 Hz, 1 H) 8.35 (s, 1 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D49 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3 H) 2.51(m, 4 H) 2.80 (t, J = 7.68 Hz, 2 H) 3.00 (t, J = 7.68 Hz, 2 H) 3.08 (m,4 H) 4.33 (s, 3 H) 4.58 (d, J = 6.22 Hz, 2 H) 6.91 (d, J = 9.02 Hz, 2 H)6.96 (dd, J = 5.06, 3.48 Hz, 1 H) 7.01 (dd, J = 3.41, 1.10 Hz, 1 H) 7.37(dd, J = 5.06, 1.28 Hz, 1 H) 7.53 (d, J = 9.15 Hz, 2 H) 8.35 (s, 1 H)8.74 (t, J = 6.22 Hz, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D68 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.89 (t, J = 7.26 Hz, 3 H) 1.86 (m, 2 H) 2.25(s, 3 H) 2.49 (m, 4 H) 2.78 (m, 2 H) 2.95 (m, 2 H) 3.08 (m, 4 H) 4.35(s, 3 H) 4.88 (m, 1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.23 (m, 1 H) 7.33 (m,2 H) 7.42 (m, 2 H) 7.53 (d, J = 9.02 Hz, 2 H) 8.34 (s, 1 H) 8.41 (d, J =8.78 Hz, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D64 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.52 (m, 4 H) 2.83 (m, 4 H) 2.90 (m, 3 H)3.09 (m, 4 H) 3.18 (s, 3 H) 4.30 (d, J = 17.68 Hz, 6 H) 4.69 (s, 2 H)4.97 (s, 2 H) 6.91 (m, J = 9.02 Hz, 2 H) 7.29 (m, 5 H) 7.52 (m, 2 H)8.36 (s, 1 H) 9.27 (s, 1 H) B10-X00-M00(C01)-D53 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.50 (d, 3 H) 2.27 (s, 3 H) 2.52 (m, 4 H) 2.78 (t, 2 H)2.95 (t, 2 H) 3.09 (m, 4 H) 4.37 (s, 3 H) 5.13 (m, 1 H) 6.93 (d, 2 H)7.41 (d, 2 H) 7.53 (d, 2 H) 8.35 (s, 1 H) 8.51 (m, 2 H) 8.66 (d, 1 H)9.26 (s, 1 H) B10-X00-M00(C01)-D52 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72(s, 6 H) 2.26 (s, 3 H) 2.50 (m, 4 H) 2.79 (t, 2 H) 2.92 (t, 2 H) 3.10(m, 4 H) 4.38 (s, 3 H) 6.94 (d, 2 H) 7.22 (m, 1 H) 7.34 (m, 2 H) 7.43(m, 2 H) 7.54 (d, 2 H) 7.81 (s, 1 H) 8.36 (s, 1 H) 9.28 (s, 1 H)B10-X00-M00(C01)-D57 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.52(m, 4 H) 2.81 (t, 2 H) 3.01 (t, 2 H) 3.09 (m, 4 H) 4.33 (s, 3 H) 4.92(d, 2 H) 6.92 (d, 2 H) 7.57 (m, 6 H) 7.85 (m, 1 H) 7.96 (m, 1 H) 8.24(m, 1 H) 8.35 (s, 1 H) 8.69 (t, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D59¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.52 (m, 4 H) 2.80 (t, J =7.68 Hz, 2 H) 2.99 (t, J = 7.62 Hz, 2 H) 3.09 (m, 4 H) 4.32 (d, J = 5.85Hz, 2 H) 4.33 (s, 3 H) 5.98 (s, 2 H) 6.80 (dd, J = 7.93, 1.59 Hz, 1 H)6.86 (d, J = 7.80 Hz, 1 H) 6.91 (d, J = 2.56 Hz, 1 H) 6.91 (d, J = 8.05Hz, 2 H) 7.54 (d, J = 9.15 Hz, 2 H) 8.35 (s, 1 H) 8.63 (t, J = 6.40 Hz,1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D37 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.49 (d, J = 7.07 Hz, 3 H) 2.27 (s, 3 H) 2.51 (m, 4 H) 2.78 (t, J = 7.68Hz, 2 H) 2.95 (t, J = 7.74 Hz, 2 H) 3.09 (m, 4 H) 4.35 (s, 3 H) 5.15 (m,1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.15 (t, J = 8.96 Hz, 2 H) 7.46 (dd, J =8.54, 5.61 Hz, 2 H) 7.53 (d, J = 9.15 Hz, 2 H) 8.34 (s, 1 H) 8.49 (d, J= 8.41 Hz, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D74 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.92 (m, 2 H) 1.18 (m, 4 H) 1.67 (m, 5 H) 2.27 (s, 3 H)2.52 (m, 4 H) 2.79 (t, 2 H) 2.98 (t, 2 H) 3.08 (m, 6 H) 4.33 (s, 3 H)6.92 (d, 2 H) 7.53 (d, 2 H) 8.05 (t, 1 H) 8.35 (s, 1 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D39 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.68 (m, 4 H) 2.24(s, 3 H) 2.52 (m, 8 H) 2.78 (t, 2 H) 2.95 (t, 2 H) 3.08 (m, 4 H) 4.36(s, 3 H) 5.11 (m, 1 H) 6.92 (d, 2 H) 7.33 (m, 3 H) 7.41 (m, 2 H) 7.52(d, 2 H) 8.34 (s, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D51 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.52 (m, 4 H) 2.79 (t, J = 7.80 Hz, 2H) 2.95 (m, 2 H) 3.09 (m, 4 H) 4.37 (s, 3 H) 5.53 (d, J = 7.80 Hz, 1 H)6.92 (d, J = 9.15 Hz, 2 H) 7.31 (m, 1 H) 7.38 (m, 2 H) 7.38 (m, 1 H)7.47 (m, 2 H) 7.54 (d, J = 9.15 Hz, 2 H) 7.86 (s, 1 H) 8.12 (d, J = 7.80Hz, 1 H) 8.35 (s, 1 H) 9.27 (s, 1 H) B10-X00-M00(C01)-D38 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.53 (m, 10 H) 2.80 (t, 2 H) 2.95 (m,4 H) 3.10 (m, 4 H) 3.58 (m, 4 H) 4.39 (s, 3 H) 5.18 (m, 1 H) 6.94 (d, 2H) 7.26 (m, 1 H) 7.35 (m, 2 H) 7.44 (m, 2 H) 7.55 (d, 2 H) 8.36 (s, 1 H)8.42 (d, 1 H) 9.28 (s, 1 H) B10-X00-M00(C01)-D62 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.52 (m, 4 H) 2.80 (t, J = 7.68 Hz, 2 H)2.98 (t, J = 7.56 Hz, 2 H) 3.09 (m, 4 H) 4.35 (s, 3 H) 6.36 (d, J = 8.78Hz, 1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.28 (m, 2 H) 7.36 (t, J = 7.50 Hz,4 H) 7.41 (m, 4 H) 7.54 (d, J = 9.15 Hz, 2 H) 8.35 (s, 1 H) 8.70 (d, J =8.90 Hz, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D75 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33 (m, 11 H) 1.12 (d, J = 6.83 Hz, 3 H) 2.26 (s, 3 H)2.51 (m, 4 H) 2.80 (t, J = 7.62 Hz, 2 H) 2.95 (m, 2 H) 3.09 (m, 4 H)3.82 (m, 1 H) 4.33 (s, 3 H) 6.91 (d, J = 9.02 Hz, 2 H) 7.54 (d, J = 9.02Hz, 2 H) 7.65 (d, J = 9.27 Hz, 1 H) 8.35 (s, 1 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D46 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.50(m, 4 H) 2.78 (t, J = 7.80 Hz, 2 H) 2.96 (m, 2 H) 3.09 (m, 4 H) 3.30 (s,3 H) 3.60 (dd, J = 9.94, 5.18 Hz, 1 H) 3.78 (dd, J = 10.00, 7.93 Hz, 1H) 4.37 (s, 3 H) 5.23 (m, 1 H) 6.92 (d, J = 9.15 Hz, 2 H) 7.30 (m, 3 H)7.43 (m, 2 H) 7.54 (d, J = 9.02 Hz, 2 H) 8.34 (s, 1 H) 8.41 (d, J = 8.54Hz, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D56 ¹H NMR (400 MHz, DMSO-d₆) δppm 0.68 (m, 6 H) 2.04 (m, 4 H) 2.25 (s, 3 H) 2.49 (m, 4 H) 2.78 (t, J =7.68 Hz, 2 H) 2.91 (t, J = 7.80 Hz, 2 H) 3.08 (m, 4 H) 4.37 (s, 3 H)6.91 (d, J = 9.15 Hz, 2 H) 7.28 (m, 5 H) 7.42 (s, 1 H) 7.54 (d, J = 9.02Hz, 2 H) 8.34 (s, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D69 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.86 (m, 4 H) 2.25 (s, 3 H) 2.49 (m, 4 H) 2.77 (m, 2H) 2.83 (t, J = 7.68 Hz, 2 H) 3.03 (m, 2 H) 3.08 (m, 4 H) 4.31 (s, 3 H)5.20 (m, 1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.16 (m, 4 H) 7.53 (d, J = 9.15Hz, 2 H) 8.14 (d, J = 9.02 Hz, 1 H) 8.36 (s, 1 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D63 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3 H) 2.49(m, 4 H) 2.80 (t, J = 7.68 Hz, 2 H) 2.99 (t, J = 7.68 Hz, 2 H) 3.08 (m,4 H) 3.15 (t, J = 8.66 Hz, 2 H) 4.33 (m, 2 H) 4.33 (s, 3 H) 4.50 (t, J =8.72 Hz, 2 H) 6.69 (d, J = 8.17 Hz, 1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.05(dd, J = 8.11, 1.89 Hz, 1 H) 7.20 (d, J = 1.22 Hz, 1 H) 7.53 (d, J =9.02 Hz, 2 H) 8.35 (s, 1 H) 8.56 (t, J = 6.34 Hz, 1 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D65 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.60 (m, 4 H) 2.25(s, 3 H) 2.48 (m, 4 H) 2.93 (m, 4 H) 3.08 (m, 4 H) 4.32 (s, 3 H) 5.52(q, J = 8.17 Hz, 1 H) 6.91 (d, J = 9.02 Hz, 2 H) 7.24 (m, 4 H) 7.54 (d,J = 9.15 Hz, 2 H) 8.27 (d, J = 8.66 Hz, 1 H) 8.36 (s, 1 H) 9.25 (s, 1 H)B10-X00-M00(C01)-D43 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (m, 4 H) 2.26(s, 3 H) 2.52 (m, 4 H) 2.79 (t, 2 H) 2.96 (t, 2 H) 3.09 (m, 4 H) 4.35(s, 3 H) 6.93 (d, 2 H) 7.16 (m, 1 H) 7.25 (m, J = 10.00 Hz, 4 H) 7.53(d, 2 H) 8.35 (s, 1 H) 8.86 (s, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D66¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.67 (s, 6 H) 2.24 (s, 3 H) 2.50 (m, 4H) 2.76 (t, 2 H) 2.88 (t, 2 H) 3.08 (m, 4 H) 4.37 (s, 3 H) 6.93 (d, 2 H)7.37 (m, 2 H) 7.52 (d, 2 H) 8.04 (s, 1 H) 8.33 (s, 1 H) 8.48 (m, 2 H)9.26 (s, 1 H) B10-X00-M00(C01)-D55 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25(s, 3 H) 2.52 (m, 4 H) 2.80 (t, 2 H) 2.99 (t, 2 H) 3.08 (m, 4 H) 4.35(s, 3 H) 4.48 (d, 2 H) 6.93 (d, 2 H) 7.18 (m, 2 H) 7.31 (m, 2 H) 7.53(d, 2 H) 8.35 (s, 1 H) 8.68 (t, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D35¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.24 (s, 3 H) 2.51 (m, 4 H) 2.80 (t, 2H) 2.99 (t, 2 H) 3.08 (m, 4 H) 3.75 (s, 3 H) 4.34 (s, 3 H) 4.39 (d, 2 H)6.83 (m, 1 H) 6.90 (m, 4 H) 7.24 (t, 1 H) 7.53 (d, 2 H) 8.35 (s, 1 H)8.67 (t, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D48 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.24 (s, 3 H) 2.47 (m, 4 H) 2.80 (t, 2 H) 2.99 (t, 2 H)3.08 (m, 4 H) 3.85 (s, 3 H) 4.35 (s, 3 H) 4.41 (d, 2 H) 6.92 (m, 3 H)7.01 (m, 1 H) 7.17 (m, 1 H) 7.24 (m, 1 H) 7.53 (d, 2 H) 8.35 (s, 1 H)8.38 (t, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D77 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.12 (t, J = 7.56 Hz, 6 H) 2.29 (s, 3 H) 2.55 (m, 4 H)2.56 (q, J = 7.68 Hz, 4 H) 2.83 (t, J = 7.62 Hz, 2 H) 3.00 (t, J = 7.62Hz, 2 H) 3.11 (m, 4 H) 4.40 (s, 3 H) 6.93 (d, J = 9.15 Hz, 2 H) 7.14 (d,J = 7.68 Hz, 2 H) 7.22 (dd, J = 8.29, 6.83 Hz, 1 H) 7.56 (d, J = 9.02Hz, 2 H) 8.37 (s, 1 H) 9.28 (s, 1 H) 9.57 (s, 1 H) B10-X00-M00(C01)-D58¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.51 (m, 4 H) 2.80 (t, J =7.74 Hz, 2 H) 2.99 (t, J = 7.62 Hz, 2 H) 3.08 (m, 4 H) 3.73 (s, 6 H)4.34 (s, 3 H) 4.36 (d, J = 6.71 Hz, 2 H) 6.38 (t, J = 2.32 Hz, 1 H) 6.50(d, J = 2.19 Hz, 2 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.54 (d, J = 9.15 Hz, 2H) 8.35 (s, 1 H) 8.64 (t, J = 6.28 Hz, 1 H) 9.26 (s, 1 H)B10-X00-M00(C01)-D20 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.52(m, 4 H) 2.84 (t, J = 7.74 Hz, 2 H) 3.05 (t, J = 7.74 Hz, 2 H) 3.09 (m,4 H) 4.41 (s, 3 H) 6.92 (d, J = 9.15 Hz, 2 H) 7.10 (tt, J = 7.39, 1.14Hz, 1 H) 7.34 (dd, J = 8.29, 7.56 Hz, 2 H) 7.55 (d, J = 9.02 Hz, 2 H)7.83 (dd, J = 8.66, 1.10 Hz, 2 H) 8.38 (s, 1 H) 9.28 (s, 1 H) 10.07 (s,1 H) B10-X00-M00(C01)-D36 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49 (m, 6 H)2.27 (s, 3 H) 2.52 (m, 10 H) 2.78 (t, 2 H) 2.95 (t, 2 H) 3.09 (m, 4 H)4.37 (s, 3 H) 5.12 (m, 1 H) 6.93 (d, 2 H) 7.24 (m, 1 H) 7.33 (m, 2 H)7.39 (m, 2 H) 7.53 (d, 2 H) 8.34 (m, 2 H) 9.26 (s, 1 H)B10-X00-M00(C01)-D70 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 2.79(t, 2 H) 2.97 (t, 2 H) 3.09 (m, 4 H) 3.35 (m, 4 H) 3.65 (dd, 1 H) 3.90(dd, 1 H) 4.37 (s, 3 H) 5.25 (m, 1 H) 6.92 (d, J = 8.78 Hz, 2 H) 7.29(m, 1 H) 7.37 (m, 2 H) 7.47 (m, 2 H) 7.53 (d, 2 H) 8.35 (s, 1 H) 8.82(d, 1 H) 9.26 (s, 1 H) B10-X00-M00(C01)-D73 ¹H NMR (400 MHz, DMSO-d₆) δppm 2.27 (s, 3 H) 2.81 (m, 4 H) 3.11 (m, 6 H) 3.34 (m, 4 H) 4.33 (s, 3H) 4.52 (m, 1 H) 5.38 (m, 1 H) 5.44 (d, 1 H) 6.92 (d, 2 H) 7.22 (m, 3 H)7.53 (d, 2 H) 7.70 (m, 1 H) 8.38 (s, 1 H) 9.27 (s, 1 H)B10-X00-M00(C01)-D165 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.04 (s, 3 H) 2.27(s, 3 H) 2.52 (m, 4 H) 2.74 (t, 2 H) 2.87 (t, 2 H) 3.09 (m, 4 H) 3.35(m, 8 H) 4.34 (s, 3 H) 6.92 (d, 2 H) 7.31 (m, 1 H) 7.43 (m, 4 H) 7.52(d, 2 H) 8.32 (s, 1 H) 9.10 (s, 1 H) 9.25 (s, 1 H) B10-X00-M00(C01)-D144¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.81 (s, 3 H) 2.24 (m, 7 H) 2.47 (m, 4H) 2.78 (m, 6 H) 3.08 (m, 4 H) 3.46 (m, 2 H) 3.55 (m, 2 H) 4.37 (s, 3 H)6.93 (d, 2 H) 7.21 (m, 1 H) 7.35 (m, 4 H) 7.54 (d, 2 H) 8.35 (m, 2 H)9.27 (s, 1 H) B10-X00-M00(C01)-D164 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27(s, 3 H) 2.52 (m, 4 H) 2.78 (t, 2 H) 2.96 (t, 2 H) 3.09 (m, 4 H) 3.55(m, 8 H) 4.34 (s, 3 H) 6.00 (d, 1 H) 6.92 (d, 2 H) 7.34 (m, 1 H) 7.43(m, 4 H) 7.52 (d, 2 H) 8.24 (d, 1 H) 8.34 (s, 1 H) 9.26 (s, 1 H)B109-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 2.53(m, 4 H) 2.83 (m, 2 H) 3.00 (m, 6 H) 4.36 (s, 3 H) 4.44 (d, J = 6.34 Hz,2 H) 7.01 (dd, J = 9.94, 8.96 Hz, 1 H) 7.27 (m, 5 H) 7.37 (dd, J = 8.29,2.19 Hz, 1 H) 7.67 (dd, J = 15.36, 2.44 Hz, 1 H) 8.41 (s, 1 H) 8.71 (t,J = 6.34 Hz, 1 H) 9.55 (s, 1 H) B109-X00-M00(C01)-D21 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.54 (m, 4 H) 2.82 (t, J = 7.68 Hz, 2 H)2.99 (m, 6 H) 4.36 (s, 3 H) 4.41 (d, J = 6.34 Hz, 2 H) 7.01 (dd, J =9.94, 8.96 Hz, 1 H) 7.15 (t, J = 8.96 Hz, 2 H) 7.37 (m, 3 H) 7.67 (dd, J= 15.43, 2.38 Hz, 1 H) 8.41 (s, 1 H) 8.75 (t, J = 6.28 Hz, 1 H) 9.55 (s,1 H) B108-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (s, 9 H)2.71 (m, 4 H) 2.80 (t, 2 H) 2.99 (t, 2 H) 3.06 (m, 4 H) 4.34 (s, 3 H)6.91 (d, 2 H) 7.25 (s, 1 H) 7.46 (s, 1 H) 7.51 d, 2 H) 8.34 (s, 1 H)9.24 (s, 1 H) B108-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07(s, 9 H) 2.71 (m, 4 H) 2.80 (t, 2 H) 2.99 (t, 2 H) 3.06 (m, 4 H) 4.34(s, 3 H) 4.42 (d, 2 H) 6.91 (d, 2 H) 7.34 (m, 5 H) 8.35 (s, 1 H) 8.69(t, 1 H) 9.24 (s, 1 H) B108-X00-M00(C01)-D44 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.08 (s, 9 H) 2.69 (m, 4 H) 2.80 (t, 2 H) 2.99 (t, 2 H) 3.06 (m, 4H) 4.36 (s, 3 H) 4.44 (d, 2 H) 6.92 (d, 2 H) 7.31 (m, 2 H) 7.54 (d, 2 H)8.35 (s, 1 H) 8.50 (m, 2 H) 8.86 (t, 1 H) 9.26 (s, 1 H)B108-X00-M00(C01)-D52 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (s, 9 H) 1.70(s, 6 H) 2.69 (m, 4 H) 2.77 (t, 2 H) 2.90 (t, 2 H) 3.06 (m, 4 H) 4.36(s, 3 H) 6.92 (d, 2 H) 7.20 (m, 1 H) 7.32 (m, 2 H) 7.41 (m, 2 H) 7.51(d, 2 H) 7.79 (s, 1 H) 8.33 (s, 1 H) 9.25 (s, 1 H) B108-X00-M00(C01)-D51¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (s, 9 H) 2.69 (s, 4 H) 2.79 (t, J =7.68 Hz, 2 H) 2.95 (t, J = 7.86 Hz, 2 H) 3.08 (s, 4 H) 4.37 (s, 3 H)5.53 (d, J = 7.80 Hz, 1 H) 6.91 (d, J = 9.15 Hz, 2 H) 7.31 (m, 1 H) 7.38(m, 3 H) 7.47 (d, J = 7.19 Hz, 2 H) 7.53 (d, J = 9.15 Hz, 2 H) 7.87 (s,1 H) 8.12 (d, J = 7.68 Hz, 1 H) 8.34 (s, 1 H) 9.26 (s, 1 H)B108-X00-M00(C01)-D38 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (s, 9 H) 2.52(m, 4 H) 2.68 (m, 4 H) 2.78 (t, 2 H) 2.92 (m, 4 H) 3.07 (m, 4 H) 3.56(m, 4 H) 4.37 (s, 3 H) 5.16 (m, 1 H) 6.92 (d, 2 H) 7.24 (m, 1 H) 7.33(m, 2 H) 7.42 (m, 2 H) 7.51 (d, 2 H) 8.34 (s, 1 H) 8.40 (d, 1 H) 9.25(s, 1 H) B108-X00-M00(C01)-D35 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (s,9 H) 2.66 (s, 4 H) 2.80 (t, J = 7.68 Hz, 2 H) 2.99 (t, J = 7.62 Hz, 2 H)3.06 (s, 4 H) 3.75 (s, 3 H) 4.34 (s, 3 H) 4.40 (d, J = 6.22 Hz, 2 H)6.82 (ddd, J = 8.20, 2.59, 0.91 Hz, 1 H) 6.90 (m, 4 H) 7.24 (t, J = 8.05Hz, 1 H) 7.53 (d, J = 8.90 Hz, 2 H) 8.35 (s, 1 H) 8.67 (t, J = 6.34 Hz,1 H) 9.25 (s, 1 H) B19-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.80 (t, 2 H) 3.00 (t, 2 H) 3.05 (m, 4 H) 3.75 (m, 4 H) 4.34 (s, 3 H)4.44 (d, 2 H) 6.94 (d, 2 H) 7.34 (m, 5 H) 7.55 (d, 2 H) 8.35 (s, 1 H)8.69 (t, 1 H) 9.28 (s, 1 H) B19-X00-M00(C01)-D21 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.80 (t, 2 H) 2.99 (t, 2 H) 3.05 (m, 4 H) 3.75 (m, 4 H)4.34 (s, 3 H) 4.41 (d, 2 H) 6.94 (d, 2 H) 7.15 (m, 2 H) 7.36 (m, 2 H)7.55 (d, 2 H) 8.35 (s, 1 H) 8.74 (t, 1 H) 9.28 (s, 1 H)B19-X00-M00(C01)-D24 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (d, 3 H) 2.79(t, 2 H) 2.96 (t, 2 H) 3.05 (m, 4 H) 3.75 (m, 4 H) 4.35 (s, 3 H) 5.15(m, 1 H) 6.94 (d, 2 H) 7.23 (m, 1 H) 7.33 (m, 2 H) 7.41 (m, 2 H) 7.55(d, 2 H) 8.35 (s, 1 H) 8.42 (d, 1 H) 9.27 (s, 1 H) B19-X00-M00(C01)-D47¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (m, 3 H) 2.78 (m, 2 H) 2.96 (m, 2H) 3.05 (m, 4 H) 3.75 (m, 4 H) 4.35 (s, 3 H) 5.15 (m, 1 H) 6.94 (m, 2 H)7.24 (t, 1 H) 7.33 (t, 2 H) 7.41 (m, 2 H) 7.55 (m, 2 H) 8.35 (s, 1 H)8.42 (s, 1 H) 9.27 (s, 1 H) B19-X00-M00(C01)-D42 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.90 (m, 4 H) 3.05 (m, 4 H) 3.76 (m, 4 H) 4.35 (s, 3 H)4.40 (m, 2 H) 6.94 (m, 2 H) 7.37 (m, 3 H) 7.55 (m, 2 H) 8.36 (s, 1 H)8.81 (m, 1 H) 9.28 (s, 1 H) B19-X00-M00(C01)-D41 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.89 (m, 3 H) 1.81 (m, 2 H) 2.78 (m, 4 H) 3.05 (m, 4 H)3.76 (m, 4 H) 4.36 (s, 3 H) 4.88 (m, 1 H) 6.93 (m, 2 H) 7.23 (m, 1 H)7.33 (m, 2 H) 7.41 (m, 2 H) 7.55 (m, 2 H) 8.34 (m, 1 H) 8.37 (d, 1 H)9.27 (s, 1 H) B19-X00-M00(C01)-D68 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.81(m, 2 H) 2.78 (m, 4 H) 3.05 (m, 4 H) 3.75 (m, 4 H) 4.36 (s, 3 H) 4.88(m, 1 H) 6.93 (m, 2 H) 7.33 (m, 5 H) 7.55 (m, 2 H) 8.34 (m, 1 H) 8.40(m, 1 H) 9.27 (m, 1 H) B19-X00-M00(C01)-D61 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.51 (m, 3 H) 2.96 (m, 4 H) 3.05 (m, 4 H) 3.75 (m, 4 H) 4.35 (s, 3H) 5.15 (m, 1 H) 6.94 (m, 2 H) 7.33 (m, 5 H) 7.55 (m, 2 H) 8.35 (s, 1 H)8.42 (m, 1 H) 9.27 (m, 1 H) B19-X00-M00(C01)-D40 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.91 (m, 4 H) 3.05 (m, 4 H) 3.75 (m, 4 H) 4.35 (s, 3 H)4.43 (m, 2 H) 6.94 (d, 2 H) 7.18 (m, 4 H) 7.55 (d, 2 H) 8.36 (s, 1 H)8.79 (s, 1 H) 9.28 (s, 1 H) B19-X00-M00(C01)-D34 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.79 (t, J = 7.68 Hz, 2 H) 2.96 (t, J = 7.74 Hz, 2 H)3.05 (m, 4 H) 3.74 (m, 6 H) 4.37 (s, 3 H) 5.02 (m, 2 H) 6.93 (d, J =9.15 Hz, 2 H) 7.24 (m, 1 H) 7.33 (m, 2 H) 7.39 (m, 2 H) 7.56 (d, J =9.02 Hz, 2 H) 8.27 (d, J = 8.29 Hz, 1 H) .35 (s, 1 H) 9.28 (s, 1 H)B19-X00-M00(C01)-D44 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.01 (m, 4 H) 3.07(s, 4 H) 3.77 (m, 4 H) 4.38 (m, 3 H) 4.46 (m, 2 H) 6.95 (m, 1 H) 7.33(m, 2 H) 7.57 (m, 2 H) 8.38 (s, 1 H) 8.58 (m, 2 H) 8.88 (m, 1 H) 9.31(s, 1 H) B19-X00-M00(C01)-D52 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70 (s, 6H) 2.77 (t, J = 7.80 Hz, 2 H) 2.90 (m, 2 H) 3.06 (m, 4 H) 3.76 (m, 4 H)4.36 (s, 3 H) 6.93 (d, J = 9.15 Hz, 2 H) 7.20 (m, 1 H) 7.32 (t, J = 7.68Hz, 2 H) 7.42 (m, 2 H) 7.56 (d, J = 9.15 Hz, 2 H) 7.79 (s, 1 H) 8.34 (s,1 H) 9.27 (s, 1 H) B19-X00-M00(C01)-D38 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.52 (m, 5 H) 2.78 (m, 5 H) 3.05 (m, 4 H) 3.56 (m, 4 H) 3.76 (m, 4 H)4.37 (s, 3 H) 5.17 (m, 1 H) 7.30 (m, 9 H) 8.34 (m, 1 H) 8.40 (m, 1 H)9.28 (s, 1 H) B19-X00-M00(C01)-D51 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.87(m, 4 H) 3.06 (m, 4 H) 3.76 (m, 4 H) 4.37 (s, 3 H) 5.54 (m, 1 H) 6.94(m, 2 H) 7.42 (m, 8 H) 7.86 (m, 1 H) 8.11 (d, 1 H) 8.35 (m, 1 H) 9.28(m, 1 H) B19-X00-M00(C01)-D39 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.69 (m, 4H) 2.52 (s, 6 H) 2.87 (d, 4 H) 3.05 (s, 4 H) 3.76 (s, 4 H) 4.37 (s, 3 H)5.10 (m, 1 H) 7.30 (m, 9 H) 8.35 (m, 2 H) 9.28 (m, 1 H)B09-X00-M00(C01)-D35 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 2.52(m, 4 H) 2.82 (t, 2 H) 3.00 (t, 2 H) 3.13 (m, 4 H) 3.75 (s, 3 H) 4.36(s, 3 H) 4.40 (d, 2 H) 6.59 (m, 1 H) 6.83 (m, 1 H) 6.90 (m, 2 H) 7.14(m, 1 H) 7.24 (m, 3 H) 8.40 (s, 1 H) 8.67 (t, 1 H) 9.33 (s, 1 H)B09-X00-M00(C01)-D34 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H) 2.52(m, 4 H) 2.80 (t, 2 H) 2.97 (t, 2 H) 3.13 (m, 4 H) 3.73 (m, 2 H) 4.39(s, 3 H) 5.00 (m, 2 H) 6.59 (m, 1 H) 7.14 (m, 1 H) 7.25 (m, 7 H) 8.26(d, 1 H) 8.40 (s, 1 H) 9.33 (s, 1 H) B09-X00-M00(C01)-D43 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.29 (m, 4 H) 2.28 (s, 3 H) 2.52 (m, 4 H) 2.81 (t, 2H) 2.97 (t, 2 H) 3.14 (m, 4 H) 4.37 (s, 3 H) 6.59 (m, 1 H) 6.71 (m, 1 H)7.24 (m, 7 H) 8.40 (s, 1 H) 8.86 (s, 1 H) 9.33 (s, 1 H)B09-X00-M00(C01)-D39 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70 (m, 4 H) 2.25(s, 3 H) 2.48 (m, 4 H) 2.83 (m, 10 H) 3.12 (m, 4 H) 4.38 (s, 3 H) 5.10(m, 1 H) 6.58 (ddd, J = 8.14, 2.29, 0.67 Hz, 1 H) 7.14 (t, J = 7.99 Hz,1 H) 7.24 (m, 3 H) 7.33 (m, 2 H) 7.42 (m, 2 H) 8.35 (d, J = 8.66 Hz, 1H) 8.39 (s, 1 H) 9.33 (s, 1 H) B09-X00-M00(C01)-D51 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.28 (s, 3 H) 2.52 (m, 4 H) 2.81 (t, J = 7.80 Hz, 2 H)2.97 (m, 2 H) 3.14 (m, 4 H) 4.39 (s, 3 H) 5.53 (d, J = 7.68 Hz, 1 H)6.58 (dd, J = 8.11, 2.26 Hz, 1 H) 7.14 (t, J = 8.05 Hz, 1 H) 7.26 (m, 2H) 7.31 (m, 1 H) 7.38 (m, 3 H) 7.48 (m, 2 H) 7.87 (s, 1 H) 8.12 (d, J =7.68 Hz, 1 H) 8.40 (s, 1 H) 9.34 (s, 1 H) B09-X00-M00(C01)-D36 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.49 (m, 6 H) 2.29 (s, 3 H) 2.49 (m, 8 H) 2.80(t, J = 7.68 Hz, 3 H) 2.97 (m, 3 H) 3.14 (m, 4 H) 4.39 (s, 3 H) 5.14 (m,1 H) 6.58 (dd, J = 8.17, 1.83 Hz, 1 H) 7.15 (t, J = 8.11 Hz, 1 H) 7.26(m, 3 H) 7.33 (t, J = 7.50 Hz, 2 H) 7.41 (m, 2 H) 8.36 (s, 1 H) 8.40 (s,1 H) 9.34 (s, 1 H) B101-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.16 (s, 3 H) 2.34 (m, 8 H) 2.83 (t, 2 H) 3.01 (t, 2 H) 3.40 (s, 2 H)4.36 (s, 3 H) 4.43 (d, 2 H) 7.23 (m, 3 H) 7.34 (m, 3 H) 7.65 (d, 2 H)8.41 (s, 1 H) 8.71 (t, 1 H) 9.50 (s, 1 H) B101-X00-M00(C01)-D44 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.16 (s, 3 H) 2.34 (m, 8 H) 2.83 (t, 2 H) 3.00(t, 2 H) 3.40 (s, 2 H) 4.38 (s, 3 H) 4.44 (d, 2 H) 7.23 (d, 2 H) 7.30(m, 2 H) 7.65 (d, 2 H) 8.41 (s, 1 H) 8.50 (m, 2 H) 8.87 (t, 1 H) 9.51(s, 1 H) B101-X00-M00(C01)-D52 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70 (s,6 H) 2.16 (s, 3 H) 2.34 (m, 8 H) 2.79 (t, 2 H) 2.91 (t, 2 H) 3.40 (s, 2H) 4.38 (s, 3 H) 7.21 (m, 3 H) 7.32 (m, 2 H) 7.42 (m, 2 H) 7.64 (d, 2 H)7.80 (s, 1 H) 8.39 (s, 1 H) 9.50 (s, 1 H) B101-X00-M00(C01)-D37 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.50 (d, 3 H) 2.16 (s, 3 H) 2.34 (m, 8 H) 2.81(t, 2 H) 2.97 (t, 2 H) 3.41 (m, 2 H) 4.37 (s, 3 H) 5.15 (m, 1 H) 7.15(dd, 2 H) 7.23 (d, 2 H) 7.46 (dd, 2 H) 7.64 (d, 2 H) 8.40 (s, 1 H) 8.50(d, 1 H) 9.49 (s, 1 H) B101-X00-M00(C01)-D51 ¹H NMR (400 MHz, DMSO-d₆) δppm 2.16 (s, 3 H) 2.34 (m, 8 H) 2.81 (t, 2 H) 2.97 (t, 2 H) 3.40 (s, 2H) 4.39 (s, 3 H) 5.52 (d, 1 H) 7.23 (d, 2 H) 7.31 (m, 1 H) 7.38 (m, 4 H)7.46 (m, 2 H) 7.64 (d, 2 H) 7.87 (s, 2 H) 8.12 (d, 1 H) 8.40 (s, 1 H)9.50 (s, 1 H) B102-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.36(m, 4 H) 2.83 (t, J = 7.74 Hz, 2 H) 3.01 (t, J = 7.68 Hz, 2 H) 3.43 (m,2 H) 3.59 (m, 4 H) 4.36 (s, 3 H) 4.44 (d, J = 6.46 Hz, 2 H) 7.25 (m, 3H) 7.32 (m, 4 H) 7.68 (d, J = 8.17 Hz, 2 H) 8.41 (s, 1 H) 8.71 (t, J =6.28 Hz, 1 H) 9.52 (s, 1 H) B102-X00-M00(C01)-D38 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.52 (m, 10 H) 2.81 (t, 2 H) 2.95 (t, 2 H) 3.43 (s, 2 H)3.59 (m, 8 H) 4.39 (s, 3 H) 5.18 (m, 1 H) 7.25 (m, 3 H) 7.33 (m, 2 H)7.42 (m, 2 H) 7.66 (d, 2 H) 8.40 (m, 2 H) 9.51 (s, 1 H)B102-X00-M00(C01)-D52 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70 (s, 6 H) 2.36(m, 4 H) 2.79 (t, 2 H) 2.91 (t, 2 H) 3.42 (s, 2 H) 3.59 (m, 4 H) 4.38(s, 3 H) 7.25 (m, 3 H) 7.32 (m, 2 H) 7.42 (m, 2 H) 7.66 (d, 2 H) 7.80(s, 1 H) 8.40 (s, 1 H) 9.51 (s, 1 H) B102-X00-M00(C01)-D51 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.37 (m, 4 H) 2.81 (t, 2 H) 2.97 (t, 2 H) 3.42 (s, 2H) 3.59 (m, 4 H) 4.39 (s, 3 H) 5.54 (d, 1 H) 7.25 (d, 2 H) 7.31 (m, 1 H)7.38 (m, 2 H) 7.46 (m, 2 H) 7.66 (d, 2 H) 7.87 (s, 2 H) 8.12 (d, 1 H)8.41 (s, 1 H) 9.52 (s, 1 H) B102-X00-M00(C01)-D43 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.26 (m, 4 H) 2.37 (m, 4 H) 2.82 (t, 2 H) 2.97 (t, 2 H)3.44 (m, 2 H) 3.59 (m, 4 H) 4.37 (s, 3 H) 7.16 (m, 1 H) 7.24 (m, 6 H)7.66 (d, 2 H) 8.40 (s, 1 H) 8.87 (s, 1 H) 9.51 (s, 1 H)B102-X00-M00(C01)-D39 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71 (m, 4 H) 2.36(m, 4 H) 2.81 (t, 2 H) 2.97 (t, 2 H) 3.35 (m, 6 H) 3.42 (s, 2 H) 3.59(m, 4 H) 4.39 (s, 3 H) 5.11 (m, 1 H) 7.25 (m, 3 H) 7.35 (m, 2 H) 7.43(m, 2 H) 7.66 (d, 2 H) 8.40 (m, 2 H) 9.51 (s, 1 H) B102-X00-M00(C01)-D36¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49 (m, 6 H) 2.38 (m, 10 H) 2.81 (t, 2H) 2.97 (t, 2 H) 3.42 (s, 2 H) 3.59 (m, 4 H) 4.39 (s, 3 H) 5.11 (m, 1 H)7.25 (m, 3 H) 7.33 (m, 2 H) 7.40 (m, 2 H) 7.66 (d, 2 H) 8.35 (d, 1 H)8.40 (s, 1 H) 9.51 (s, 1 H) B105-X00-M00(C01)-D35 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.38 (m, 4 H) 2.92 (m, 4 H) 3.44 (m, 2 H) 3.59 (m, 4 H)3.75 (s, 3 H) 4.39 (m, 5 H) 6.90 (m, 4 H) 7.25 (m, 2 H) 7.57 (m, 1 H)7.77 (m, 1 H) 8.42 (m, 1 H) 8.68 (s, 1 H) 9.54 (m, 1 H)B105-X00-M00(C01)-D51 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.38 (m, 4 H) 2.90(m, 4 H) 3.44 (m, 2 H) 3.59 (m, 4 H) 4.42 (s, 3 H) 5.53 (m, 1 H) 6.93(m, 1 H) 7.47 (m, 8 H) 7.82 (m, J = 39.51 Hz, 2 H) 8.12 (m, 1 H) 8.42(m, 1 H) 9.55 (m, 1 H) B105-X00-M00(C01)-D39 ¹H NMR (400 MHz, DMSO-d₆) δppm 2.09 (m, 4 H) 2.38 (m, 4 H) 2.90 (m, 4 H) 3.45 (m, 4 H) 3.59 (m, 4H) 4.42 (s, 3 H) 6.93 (m, 1 H) 7.25 (m, 7 H) 7.57 (m, 1 H) 7.76 (m, 1 H)8.42 (m, 1 H) 9.54 (m, 1 H) B105-X00-M00(C01)-D34 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.38 (m, 4 H) 2.90 (m, 4 H) 3.45 (m, 2 H) 3.60 (m, 4 H)3.73 (m, 2 H) 4.42 (m, 3 H) 5.00 (m, 2 H) 6.92 (m, 1 H) 7.32 (m, 6 H)7.57 (m, 1 H) 7.77 (m, 1 H) 8.27 (m, 1 H) 8.42 (m, 1 H) 9.54 (m, 1 H)B105-X00-M00(C01)-D43 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (m, 4 H) 2.38(m, 4 H) 2.98 (m, 4 H) 3.44 (m, 2 H) 3.60 (m, 4 H) 4.40 (s, 3 H) 6.92(m, 1 H) 7.20 (m, 6 H) 7.58 (m, 1 H) 7.77 (s, 1 H) 8.42 (s, 1 H) 9.20(m, 2 H) B105-X00-M00(C01)-D36 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49 (m,6 H) 2.52 (m, 8 H) 2.81 (m, 4 H) 3.45 (m, 2 H) 3.60 (s, 4 H) 4.42 (s, 3H) 5.11 (m, 1 H) 6.92 (m, 1 H) 7.25 (m, 6 H) 7.57 (m, 1 H) 7.76 (m, 1 H)8.34 (m, 1 H) 8.42 (m, 1 H) 9.54 (m, 1 H) B104-X00-M00(C01)-D52 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.71 (s, 6 H) 2.21 (s, 3 H) 2.40 (m, 8 H) 2.80(t, 2 H) 2.92 (t, 2 H) 3.44 (s, 2 H) 4.40 (s, 3 H) 6.91 (m, 1 H) 7.32(m, 4 H) 7.42 (m, 2 H) 7.55 (m, 1 H) 7.75 (m, 1 H) 7.81 (m, 1 H) 8.41(s, 1 H) 9.53 (s, 1 H) B104-X00-M00(C01)-D43 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.29 (m, 4 H) 2.20 (m, 3 H) 2.40 (m, 8 H) 2.82 (t, 2 H) 2.98 (t, 2H) 3.44 (s, 2 H) 4.39 (s, 3 H) 6.90 (m, 1 H) 7.25 (m, 6 H) 7.56 (m, 1 H)7.76 (m, 1 H) 8.42 (s, 1 H) 8.87 (s, 1 H) 9.53 (s, 1 H)B104-X00-M00(C01)-D51 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (s, 3 H) 2.42(m, 8 H) 2.82 (t, 2 H) 2.97 (t, 2 H) 3.44 (s, 2 H) 4.41 (s, 3 H) 5.53(d, 1 H) 6.91 (d, 1 H) 7.24 (m, 1 H) 7.38 (m, 3 H) 7.46 (m, 2 H) 7.56(m, 1 H) 7.75 (m, 1 H) 7.87 (s, 2 H) 8.12 (m, 1 H) 8.42 (s, 1 H) 9.54(s, 1 H) B104-X00-M00(C01)-D35 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.19 (s,3 H) 2.39 (m, 8 H) 2.83 (t, 2 H) 3.01 (t, 2 H) 3.43 (s, 2 H) 3.75 (s, 3H) 4.38 (s, 3 H) 4.41 (d, 2 H) 6.83 (m, 1 H) 6.90 (m, 3 H) 7.24 (m, 2 H)7.56 (m, 1 H) 7.76 (m, 1 H) 8.42 (s, 1 H) 8.68 (t, 1 H) 9.53 (s, 1 H)B103-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.74 (m, 1 H) 1.95(m, 1 H) 2.09 (m, 1 H) 2.26 (m, 1 H) 2.82 (m, 5 H) 3.00 (t, 2 H) 3.34(m, 4 H) 4.34 (s, 3 H) 4.43 (d, 2 H) 4.65 (m, 1 H) 7.02 (m, 2 H) 7.25(m, 1 H) 7.33 (m, 4 H) 7.62 (m, 2 H) 8.38 (s, 1 H) 8.67 (t, 1 H) 9.39(s, 1 H) B103-X00-M00(C01)-D52 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70 (s,6 H) 1.79 (m, 2 H) 2.00 (m, 2 H) 2.56 (s, 3 H) 2.68 (m, 2 H) 2.78 (t, 2H) 2.90 (t, 2 H) 2.99 (m, 2 H) 4.35 (s, 3 H) 4.42 (m, 1 H) 6.97 (d, 2 H)7.21 (m, 1 H) 7.32 (m, 2 H) 7.41 (m, 2 H) 7.58 (d, 2 H) 7.78 (s, 1 H)8.35 (s, 1 H) 9.34 (s, 1 H) B103-X00-M00(C01)-D37 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.48 (d, 3 H) 1.84 (m, 2 H) 2.01 (m, 2 H) 2.79 (m, 4 H)2.96 (m, 4 H) 4.34 (s, 3 H) 4.43 (m, 1 H) 5.15 (m, 1 H) 6.97 (d, 2 H)7.15 (m, 2 H) 7.46 (m, 2 H) 7.58 (d, 2 H) 8.36 (s, 1 H) 8.47 (d, 1 H)9.34 (s, 1 H) B103-X00-M00(C01)-D51 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71(m, 2 H) 1.96 (m, 2 H) 2.34 (s, 3 H) 2.42 (m, 2 H) 2.79 (m, 6 H) 4.36(m, 4 H) 5.52 (d, 1 H) 6.94 (d, 2 H) 7.31 (m, 1 H) 7.38 (m, 2 H) 7.46(m, 2 H) 7.56 (d, 2 H) 7.87 (s, 2 H) 8.11 (d, 1 H) 8.36 (s, 1 H) 9.34(s, 1 H) B103-X00-M00(C01)-D44 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.69 (m,2 H) 1.94 (m, 2 H) 2.32 (s, 3 H) 2.39 (m, 2 H) 2.80 (m, 4 H) 2.99 (t, 2H) 4.35 (m, 4 H) 4.44 (d, 2 H) 6.94 (d, 2 H) 7.31 (m, 2 H) 7.57 (d, 2 H)8.37 (s, 1 H) 8.50 (m, 2 H) 8.85 (t, 1 H) 9.34 (s, 1 H)B103-X00-M00(C01)-D36 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (m, 4 H) 2.20(m, 3 H) 2.37 (m, 4 H) 2.55 (m, 4 H) 2.88 (m, J = 59.63 Hz, 6 H) 4.28(m, 1 H) 4.35 (s, 3 H) 5.10 (m, 1 H) 5.35 (none, 1 H) 6.93 (m, 2 H) 7.31(m, 5 H) 7.56 (m, 2 H) 8.35 (m, 2 H) 9.32 (m, 6 H) B103-X00-M00(C01)-D39¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.68 (s, 4 H) 1.91 (m, 4 H) 2.20 (m, 3H) 2.52 (m, 8 H) 2.87 (m, J = 66.33 Hz, 4 H) 3.04 (m, 2 H) 4.28 (m, 1 H)4.35 (s, 3 H) 5.08 (m, 1 H) 6.93 (m, 2 H) 7.38 (m, 7 H) 8.35 (m, 2 H)9.32 (m, 1 H) B103-X00-M00(C01)-D34 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78(m, J = 106.57 Hz, 4 H) 2.41 (m, 7 H) 2.87 (m, J = 68.16 Hz, 4 H) 3.73(m, 2 H) 4.28 (m, 1 H) 4.36 (s, 3 H) 5.00 (m, 2 H) 6.93 (m, 2 H) 7.32(m, 5 H) 7.56 (m, 2 H) 8.26 (m, 1 H) 8.36 (m, 1 H) 9.32 (m, 1 H)B103-X00-M00(C01)-D43 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (m, 4 H) 1.79(m, J = 107.43 Hz, 4 H) 2.43 (m, 7 H) 2.88 (m, J = 66.33 Hz, 4 H) 4.29(m, 1 H) 4.34 (m, 3 H) 6.93 (m, 2 H) 7.22 (m, 5 H) 7.56 (m, 2 H) 8.36(s, 1 H) 8.86 (m, 1 H) 9.32 (m, 1 H) B00-X00-M00(C01)-D38 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.52 (m, 6 H) 2.71 (t, 2 H) 2.90 (t, 2 H) 3.57 (m, 4H) 4.36 (m, 3 H) 5.15 (m, 1 H) 6.55 (s, 2 H) 7.24 (m, 1 H) 7.33 (m, 2 H)7.41 (m, 2 H) 8.17 (s, 1 H) 8.36 (d, 1 H). B00-X00-M00(C01)-D44 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.71 (t, 2 H) 2.94 (t, 2 H) 4.35 (s, 3 H) 4.43(d, 2 H) 6.56 (s, 2 H) 7.31 (m, 2 H) 8.18 (s, 1 H) 8.50 (m, 2 H) 8.82(t, 1 H). B113-X00-M00(C01)-D44 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.83 (t,2 H) 3.00 (t, 2 H) 4.35 (s, 3 H) 4.44 (d, 2 H) 7.16 (m, 2 H) 7.30 (m, 2H) 7.71 (m, 2 H) 8.41 (s, 1 H) 8.50 (m, 2 H) 8.87 (t, 1 H) 9.55 (s, 1 H)B112-X00-M00(C01)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84 (t, J = 7.68Hz, 2 H) 3.01 (t, J = 7.68 Hz, 2 H) 4.35 (s, 3 H) 4.44 (d, J = 6.34 Hz,2 H) 7.26 (m, 5 H) 7.36 (d, J = 9.02 Hz, 2 H) 7.76 (d, J = 9.02 Hz, 2 H)8.44 (s, 1 H) 8.72 (t, J = 6.40 Hz, 1 H) 9.68 (s, 1 H)B04-X04-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.87 (t, 2 H) 2.99(t, 2 H) 3.71 (s, 3 H) 7.25 (m, 1 H) 7.44 (s, 1 H) 7.51 (m, 3 H) 7.66(m, 2 H) 8.55 (s, 1 H) B10-X00-M04(C15)-D03 ¹H NMR (400 MHz, DMSO-d₆) δppm 2.85 (m, 6 H) 3.05 (m, 4 H) 3.33 (m, 5 H) 6.28 (s, 2 H) 6.80 (d, 2H) 7.33 (s, 2 H) 7.47 (m, 7 H) 7.63 (d, 2 H) 7.66 (s, 1 H) 8.42 (s, 1 H)9.34 (s, 1 H) B09-X00-M04(C03)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79(m, 9 H) 1.64 (t, 2 H) 2.86 (m, 15 H) 4.84 (t, 2 H) 6.67 (m, 1 H) 7.21(m, 3 H) 7.39 (s, 2 H) 8.41 (s, 1 H) 9.25 (s, 1 H) B10-X00-M00(C14)-D03¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (t, 3 H) 2.25 (s, 3 H) 2.52 (m, 4H) 2.61 (q, 2 H) 2.84 (t, 2 H) 3.03 (m, 6 H) 6.16 (s, 2 H) 6.75 (d, 2 H)6.83 (s, 1 H) 7.29 (br. s, 2 H) 7.36 (d, 2 H) 7.45 (br. s, 1 H) 8.38 (s,1 H) 9.25 (s, 1 H) B10-X00-M00(C14)-D09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.12 (t, 3 H) 2.24 (s, 3 H) 2.46 (m, 4 H) 2.60 (q, 2 H) 2.85 (t, 2 H)3.02 (m, 6 H) 4.41 (d, 2 H) 6.18 (s, 2 H) 6.74 (d, 2 H) 6.83 (s, 1 H)7.23 (m, 1 H) 7.31 (m, 4 H) 7.37 (d, 2 H) 8.38 (s, 1 H) 8.69 (t, 1 H)9.26 (s, 1 H) B08-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.79(m, 2 H) 2.96 (m, 2 H) 3.83 (s, 3 H) 4.23 (s, 3 H) 6.96 (m, 3 H) 7.22(s, 1 H) 7.43 (s, 1 H) 8.00 (m, 1 H) 8.11 (s, 1 H) 8.35 (s, 1 H)B36-X00-M00(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.78 (t, 2 H) 2.95(t, 2 H) 4.28 (s, 3 H) 5.95 (s, 2 H) 6.84 (d, 1 H) 7.06 (dd, 1 H) 7.22(s, 1 H) 7.34 (d, 1 H) 7.42 (s, 1 H) 8.34 (s, 1 H) 9.34 (s, 1 H)

Example 528-iodo-1-methyl-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

To a well stirred and warm suspension of8-amino-1-methyl-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(3 g, 6.92 mmol) in dimethoxyethane (240 mL), maintained in an inertatmosphere of argon, cesium iodide (2.16 g, 8.3 mmol), bisublimatediodine (870 mg, 3.46 mmol), copper iodide (460 mg, 2.42 mmol) andisopentyl nitrite (1.71 mL, 1.5 g, 12.46 mmol) were added, in sequence.The reaction mixture was stirred vigorously at 65-70° C. for 18 hours.After cooling in an ice-water bath, the solid was filtered off and thefiltrate was diluted with dichloromethane (100 mL), washed with 30%ammonium hydroxide (50 mL), sodium thiosulphate (100 mL), brine anddried over anhydrous Na₂SO₄. The crude was purified by flashchromatography on silica gel (eluant: dichloromethane/methanol 95:59)and 1.48 g of the title compound was isolated (40% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.52 (m, 6H) 2.89 (t, 2H) 2.99 (t, 2H)4.30 (s, 3H) 5.17 (m, 1H) 7.22 (m, 1H) 7.34 (m, 2H) 7.41 (m, 2H) 8.47(s, 1H)

Example 531-methyl-8-{[3-(4-methylpiperazin-1-yl)phenyl]amino}-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B09-X00-M00(C01)-D38]

Palladium acetate [Pd(OAc)₂] (10 mg, 0.022 mmol, 10%), (±)-BINAP (14 mg,0.022 mmol, 10%) and dimethylformamide (4 mL) were charged in around-bottom flask flushed with argon. The mixture was stirred underargon for 30 minutes. Then, 3-(4-methylpiperazin-1-yl)phenylamine (84mg, 0.44 mmol),8-iodo-1-methyl-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide(120 mg, 0.22 mmol), potassium carbonate (670 mg, 4.85 mmol) anddimethylformamide (1.5 mL) were added. The resulting mixture was heatedat 80° C. in an oil bath under argon with good stirring for 1.5 hours.

After cooling to room temperature, the reaction mixture was poured intowater and extracted with dichloromethane. The organic extracts werewashed with brine and dried over Na₂SO₄. The solvent was removed undervacuo, the crude was purified by flash chromatography on silica gel(eluant: dichloromethane/methanol 95:5) to afford 40 mg (30% yield) ofthe title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3H) 2.52 (m, 8H) 2.80 (t, 2H)2.94 (m, 4H) 3.13 (m, 4H) 3.56 (m, 4H) 4.39 (s, 3H) 5.16 (m, 1H) 6.59(m, 1H) 7.14 (m, 1H) 7.24 (m, 2H) 7.33 (m, 2H) 7.42 (m, 2H) 8.39 (m, 2H)9.33 (s, 1H).

By working analogously the following compounds were prepared:

TABLE XIV B107-X00-M00(C01)-D38 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.52 (m,6 H) 2.80 (t, 2 H) 2.97 (m, 2 H) 3.09 (m, 4 H) 3.57 (m, 4 H) 3.76 (m, 4H) 4.39 (s, 3 H) 5.18 (m, 1 H) 6.60 (m, 1 H) 7.16 (m, 1 H) 7.42 (m, 6 H)8.40 (m, 2 H) 9.35 (s, 1 H) B105-X00-M00(C01)-D38 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.52 (m, 10 H) 2.81 (t, 2 H) 2.97 (t, 2 H) 3.34 (m, 10 H)4.41 (s, 3 H) 5.17 (m, 1 H) 6.93 (m, 1 H) 7.34 (m, 4 H) 7.42 (m, 2 H)7.58 (m, 1 H) 7.77 (m, 1 H) 8.41 (m, 2 H) 9.54 (s, 1 H)B103-X00-M00(C01)-D38 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66 (m, 2 H) 1.92(m, 2 H) 2.21 (m, 5 H) 2.52 (m, 4 H) 2.65 (m, 2 H) 2.79 (t, 2 H) 2.95(m, 4 H) 3.56 (m, 4 H) 4.29 (m, 1 H) 4.36 (s, 3 H) 5.17 (m, 1 H) 6.93(d, 2 H) 7.24 (m, 1 H) 7.33 (m, 2 H) 7.42 (m, 2 H) 7.56 (d, 2 H) 8.35(s, 1 H) 8.40 (d, 1 H) 9.32 (s, 1 H) B101-X00-M00(C01)-D38 ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.19 (s, 3 H) 2.52 (m, 8 H) 2.80 (t, 2 H) 2.95 (m, 4H) 3.33 (m, 6 H) 3.56 (m, 4 H) 4.39 (s, 3 H) 5.17 (m, 1 H) 7.23 (m, 3 H)7.33 (m, 2 H) 7.42 (m, 2 H) 7.65 (d, 2 H) 8.40 (m, 2 H) 9.50 (s, 1 H)B104-X00-M00(C01)-D38 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21 (s, 3 H) 2.42(m, 13 H) 2.81 (t, J = 7.80 Hz, 2 H) 2.95 (m, 3 H) 3.44 (s, 2 H) 3.57(m, 4 H) 4.41 (s, 3 H) 5.17 (m, 1 H) 6.90 (d, J = 7.56 Hz, 1 H) 7.24 (t,J = 7.68 Hz, 2 H) 7.33 (t, J = 7.50 Hz, 2 H) 7.43 (m, 2 H) 7.57 (dd, J =8.29, 0.98 Hz, 1 H) 7.76 (t, J = 1.95 Hz, 1 H) 8.41 (d, J = 7.68 Hz, 1H) 8.41 (s, 1 H) 9.53 (s, 1 H) B110-X00-M00(C01)-D38 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.45 (m, 6 H) 2.73 (m, 16 H) 3.57 (m, 4 H) 4.39 (s, 3 H)5.17 (m, 1 H) 7.26 (m, 2 H) 7.25 (m, 1 H) 7.33 (t, J = 7.56 Hz, 2 H)7.43 (m, 2 H) 7.70 (s, 2 H) 8.42 (m, 2 H) 9.55 (s, 1 H)B106-X00-M00(C01)-D38 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.74 (m, 2 H) 1.98(m, 2 H) 2.52 (m, 7 H) 2.81 (m, 8 H) 3.56 (m, 4 H) 4.41 (m, 4 H) 5.17(m, 1 H) 6.60 (m, 1 H) 7.26 (m, 5 H) 7.44 (m, 3 H) 8.42 (m, 2 H) 9.50(s, 1 H) B111-X00-M00(C01)-D38 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (t,J = 7.19 Hz, 3 H) 2.46 (m, 5 H) 2.80 (t, J = 7.74 Hz, 2 H) 2.93 (m, 3 H)3.56 (q, 4 H) 4.03 (q, J = 7.19 Hz, 2 H) 4.20 (s, 3 H) 5.16 (m, 1 H)6.20 (d, J = 1.71 Hz, 1 H) 7.24 (t, J = 7.32 Hz, 1 H) 7.33 (t, J = 7.44Hz, 2 H) 7.42 (m, 3 H) 8.36 (s, 1 H) 8.41 (d, J = 6.95 Hz, 1 H) 9.23 (s,1 H)

Example 54

Step 1.N-[(1S)-2-amino-1-phenylethyl]-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B10-X00-M00(C01)-D71]

To a solution of 129 mg (0.228 mmol) ofN-[(1S)-2-azido-1-phenylethyl]-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidein 16 mL of methanol, 65 mg (1.2 mmol) of NH₄Cl dissolved in 3.2 mL ofwater and 39 mg of iron (0.7 mmol) were added and the mixture refluxedovernight. The suspension was cooled to room temperature and filtered.After removal of methanol, solid Na₂CO₃ was added portionwise to theaqueous phase up to pH 10 and the product was then extracted withdichloromethane. Flash chromatography of the crude (eluantdichloromethane/methanol 95/5) yielded 94 mg of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.24 (s, 3H) 2.47 (m, 4H) 2.78 (t,J=7.68 Hz, 2H) 2.96 (m, 3H) 3.08 (m, 5H) 4.37 (s, 3H) 5.01 (m, 1H) 6.91(d, J=9.15 Hz, 2H) 7.31 (m, 5H) 7.54 (d, J=9.02 Hz, 2H) 8.34 (s, 1H)8.54 (d, J=8.17 Hz, 1H) 9.26 (s, 1H).

By working according to the above method the following compound wasprepared:

-   B10-X00-M03(C01)-D71

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (s, 3H) 1.34 (s, 3H) 2.24 (s, 3H)2.45-2.49 (m, 4H) 2.62-2.72 (m, 2H) 2.90-3.05 (m, 2H) 3.06-3.10 (m, 4H)4.35 (s, 3H) 5.01 (td, J=8.20, 5.67 Hz, 1H) 6.91 (d, J=9.15 Hz, 2H)7.24-7.29 (m, 1H) 7.33-7.38 (m, 2H) 7.38-7.41 (m, 2H) 7.53 (d, J=9.15Hz, 2H) 8.34 (s, 1H) 8.65 (d, J=8.29 Hz, 1H) 9.26 (s, 1H).

Step 2.N-[(1S)-2-(dimethylamino)-1-phenylethyl]-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B10-X00-M00(C01)-D72]

To a solution of 50 mg (0.091 mmol) ofN-[(1S)-2-amino-1-phenylethyl]-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidein methanol (5 mL), 0.027 mL of formaldehyde (40% aqueous solution 0.364mmol) and acetic acid (0.02 mL) were added. After 30 minutes, 77 mg(0.364 mmol) of sodiumtriacetoxyborohydride were added and the mixturewas stirred for 5 hours. The solvent was removed under vacuo, the crudewas dissolved in water and Na₂CO₃ was added portionwise up to basic pH.The product was extracted with dichloromethane as the sole compound (34mg, 66% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 9H) 2.52 (m, 4H) 2.78 (t, 2H)2.95 (t, 2H) 3.09 (m, 4H) 4.37 (s, 3H) 5.11 (m, 1H) 6.93 (d, 2H) 7.24(m, 1H) 7.33 (m, 2H) 7.41 (m, 2H) 7.53 (d, 2H) 8.34 (m, 2H) 9.26 (s,1H).

By working analogously the following compounds were prepared:

1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-N-{(1S)-2-[(1-methylpiperidin-4-yl)amino]-1-phenylethyl}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B10-X00-M00(C01)-D145]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.76 (m, 4H) 2.73 (m, 24H) 4.39 (s, 3H)5.34 (m, 1H) 6.98 (d, 2H) 7.30 (m, 1H) 7.38 (m, 2H) 7.43 (m, 2H) 7.57(d, 2H) 8.36 (s, 1H) 8.75 (s, 1H) 9.33 (bs, 1H)

-   B10-X00-M03(C01)-D72

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (s, 3H) 1.32 (s, 3H) 2.24 (s, 6H)2.25 (s, 3H) 2.49 (m, 4H) 2.67 (m, 2H) 2.80 (m, 2H) 3.08 (m, 4H) 4.34(s, 3H) 5.12 (td, J=8.20, 5.67 Hz, 1H) 6.91 (d, J=9.15 Hz, 2H) 7.25 (m,1H) 7.34 (m, 2H) 7.42 (m, 2H) 7.53 (d, J=9.15 Hz, 2H) 8.33 (s, 1H) 8.45(d, J=8.29 Hz, 1H) 9.26 (s, 1H)

Example 55N-benzyl-1-methyl-8-{[4-(4-methyl-4-oxidopiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

To a solution of 39.4 mg (0.0774 mmol) ofN-benzyl-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide,17.4 mg (0.0774 mg) of 3-chlorobenzenecarboperoxoic acid were added andthe mixture was stirred at room temperature. After 45 minutes an aqueoussolution of NaHCO₃ was added and the solvent removed. Treatment withmethanol and filtration afforded 26.6 mg of the title compound (66%yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.81 (t, J=7.74 Hz, 2H) 3.00 (t, J=7.62Hz, 2H) 3.37 (m, 8H) 3.15 (s, 3H) 4.34 (s, 3H) 4.43 (d, J=6.34 Hz, 2H)6.98 (d, J=9.15 Hz, 2H) 7.24 (m, 1H) 7.33 (m, 4H) 7.57 (d, J=9.15 Hz,2H) 8.36 (s, 1H) 8.70 (t, J=6.34 Hz, 1H) 9.30 (s, 1H).

Example 56 Ethyl8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate[B10-X00-M03(C01)-D01]

Pd(OAc)₂ (762.34 mg, 3.395 mmol), (±)-BINAP (2.145 g, 3.395 mmol) anddimethylformamide (250 mL) were charged in a round-bottom flask flushedwith argon. The mixture was stirred under argon for 30 minutes. Then4-(4-methyl-piperazin-1-yl)-phenylamine (19.493 g, 101.908 mmol), ethyl8-iodo-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(14.00 g, 33.961 mmol), K₂CO₃ (60.00 g, 434.112 mmol) anddimethylformamide (250 mL) were added. The resulting mixture was stirredat room temperature for 1 hour and then heated to 80° C. in an oil bathunder argon with good stirring for 3 hours.

After cooling to room temperature, the reaction mixture was filtered bysuction filtration washing with dichloromethane and the filtrate wasevaporated to dryness. The crude was purified by flash chromatography onsilica gel (eluant: dichloromethane/methanol 94:6) to afford 11.60 g(yield 72%) of pure title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J=7.07 Hz, 3H) 1.33 (s, 6H)2.27 (s, 3H) 2.52 (m, 4H) 2.71 (s, 2H) 3.03-3.15 (m, 4H) 4.32 (q, J=7.07Hz, 2H) 4.33 (s, 3H) 6.91 (d, J=9.02 Hz, 2H) 7.53 (d, J=9.02 Hz, 2H)8.35 (s, 1H) 9.28 (s, 1H).

By working according to the above method the following compound wasprepared:

TABLE XV B19-X00- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (t, J = 7.07M00(C01)-D01 Hz, 3 H) 1.33 (s, 6 H) 2.71 (s, 2 H) 3.01-3.08 (m, 4 H)3.70-3.80 (m, 4 H) 4.32 (q, J = 7.07 Hz, 2 H) 4.33 (s, 3 H) 6.93 (d, J =9.15 Hz, 2 H) 7.55 (d, J = 9.02 Hz, 2 H) 8.36 (s, 1 H) 9.30 (s, 1 H)

Example 578-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid potassium salt [B10-X00-M03(C01)-D02]

To a suspension of ethyl8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(11.60 g, 24.390 mmol) in anhydrous ethanol (450 mL), 1.5 M potassiumhydroxide in 95% ethanol (63 mL) was added under good stirring and themixture was heated to reflux for 3 hours. After cooling in an ice bath,a solid was formed, that was filtered washing with ethanol, dried at 40°C. under vacuum to yield 11.8 g (quantitative yield) of white solidtitle compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (s, 6H) 2.23 (s, 3H) 2.47 (m, 4H)2.58 (s, 2H) 3.03-3.15 (m, 4H) 4.17 (s, 3H) 6.91 (d, J=9.02 Hz, 2H) 7.54(d, J=9.02 Hz, 2H) 8.24 (s, 1H) 9.12 (s, 1H)

By working according to the above method the following compounds wereprepared:

TABLE XVI B04-X00-M03(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s,6 H) 2.73 (s, 2 H) 4.34 (s, 3 H) 6.98 (tt, J 7.36, 1.13, 1.10 Hz, 1 H)7.31 (dd, J 8.47, 7.38 Hz, 2 H) 7.71 (dd, J 8.66, 0.98 Hz, 2 H) 8.42 (s,1 H) 9.53 (s, 1 H) 12.84 (s, 1 H) B12-X00-M03(C01)-D02 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.31 (s, 6 H) 2.24 (s, 3 H) 2.45 (s, 4 H) 2.61 (s, 2 H)2.84 (t, J 4.51 Hz, 4 H) 4.18 (s, 3 H) 7.52 (d, J 9.02 Hz, 1 H) 7.94(dd, J 8.90, 2.44 Hz, 1 H) 8.09 (d, J 2.56 Hz, 1 H) 8.34 (s, 1 H) 9.63(s, 1 H) B13-X00-M03(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (s, 6H) 2.25 (s, 3 H) 2.52 (m, 4 H) 2.61 (s, 2 H) 2.94 (t, J 4.51 Hz, 4 H)4.20 (s, 3 H) 7.12 (d, J 8.90 Hz, 1 H) 7.53 (dd, J 8.78, 2.56 Hz, 1 H)7.99 (d, J 2.56 Hz, 1 H) 8.31 (s, 1 H) 9.45 (s, 1 H)B00-X00-M03(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (s, 6 H) 2.51(s, 2 H) 4.16 (s, 3 H) 6.37 (s, 2 H) 8.07 (s, 1 H) B19-X00-M03(C01)-D02¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (s, 6 H) 2.58 (s, 2 H) 3.01-3.09(m, 4 H) 3.71-3.79 (m, 4 H) 4.18 (s, 3 H) 6.91 (d, J = 9.15 Hz, 2 H)7.57 (d, J = 9.15 Hz, 2 H) 8.25 (s, 1 H) 9.14 (s, 1 H)B109-X00-M00(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.24 (s, 3 H) 2.48(m, 4 H) 2.76 (t, J = 7.68 Hz, 2 H) 2.96 (m, 6 H) 4.27 (s, 3 H) 6.99(dd, J = 10.00, 8.90 Hz, 1 H) 7.38 (ddd, J = 8.87, 2.47, 0.85 Hz, 1 H)7.68 (dd, J = 15.49, 2.44 Hz, 1 H) 8.34 (s, 1 H) 9.45 (s, 1 H)B13-X00-M02(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6 H) 2.25(s, 3 H) 2.51 (m, 4 H) 2.91 (s, 2 H) 2.94 (t, J 4.39 Hz, 4 H) 4.25 (s, 3H) 7.13 (d, J 8.78 Hz, 1 H) 7.53 (dd, J 8.78, 2.56 Hz, 1 H) 8.00 (d, J2.44 Hz, 1 H) 8.43 (s, 1 H) 9.49 (s, 1 H) B12-X00-M02(C01)-D02 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6 H) 2.24 (s, 3 H) 2.45 (s, 4 H) 2.84(t, J 4.63 Hz, 4 H) 2.91 (s, 2 H) 4.23 (s, 3 H) 7.52 (d, J 8.78 Hz, 1 H)7.93 (dd, J 8.78, 2.32 Hz, 1 H) 8.11 (d, J 2.56 Hz, 1 H) 8.44 (s, 1 H)9.67 (s, 1 H) B04-X00-M02(C01)-D02 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31(s, 6 H) 2.92 (s, 2 H) 4.37 (s, 3 H) 6.98 (tt, J 7.33, 1.10, 1.07 Hz, 1H) 7.32 (dd, J 8.41, 7.44 Hz, 2 H) 7.72 (dd, J 8.66, 0.98 Hz, 2 H) 8.52(s, 1 H) 9.56 (s, 1 H) 12.80 (s, 1 H) B10-X00-M02(C01)-D02 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.25 (s, 6 H) 2.23 (s, 3 H) 2.47 (m, 4 H) 2.89 (s, 2H) 3.07 (m, 4 H) 4.21 (s, 3 H) 6.89 (d, J = 9.17 Hz, 2 H) 7.54 (d, J =9.17 Hz, 2 H) 8.35 (s, 1 H) 9.14 (s, 1 H)

Example 588-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide [B10-X00-M03(C01)-D04]

To a suspension of8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid potassium salt (9.5 g, 19.561 mmol) in a 1:1 mixture of anhydroustetrahydrofurane and dimethylformamide (50 mL), 2M methylamine intetrahydrofurane (21.12 mL, 42.24 mmol), 1-hydroxybenzotriazole (5.332g, 39.458 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC)(7.567 g, 39.473 mmol) were added in that order, and the reactionmixture stirred at room temperature for 18 hours.

The reaction mixture was poured into water (2.5 L) and extracted withdichloromethane (4×250 mL). The combined organic extracts were washedwith water, essicated over anhydrous sodium sulphate, and the solventwas removed under reduced pressure. The crude was purified by flashchromatography on silica gel (eluant: methylene chloride/methanol 94:6)to afford 8.20 g (yield 92%) of pure title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 6H) 2.26 (s, 3H) 2.44-2.54 (m,4H) 2.68 (s, 2H) 2.76 (d, J=4.76 Hz, 3H) 3.04-3.13 (m, 4H) 4.31 (s, 3H)6.91 (d, J=9.02 Hz, 2H) 7.53 (d, J=9.02 Hz, 2H) 8.15 (q, J=4.84 Hz, 1H)8.34 (s, 1H) 9.25 (s, 1H)

By working according to the above method the following compounds wereprepared:

TABLE XVII B19-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s,6 H) 2.68 (s, 2 H) 2.76 (d, J = 4.76 Hz, 3 H) 3.02-3.09 (m, 4 H)3.72-3.79 (m, 4 H) 4.31 (s, 3 H) 6.93 (d, J = 9.02 Hz, 2 H) 7.55 (d, J =9.02 Hz, 2 H) 8.15 (q, J = 4.63 Hz, 1 H) 8.34 (s, 1 H) 9.28 (s, 1 H)B10-X00-M03(C01)-D25 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s, 6 H) 2.28(s, 3 H) 2.50-2.57 (m, 4 H) 2.70 (s, 2 H) 3.04- 3.13 (m, 4 H) 4.26 (d, J= 5.85 Hz, 2 H) 4.34 (s, 3 H) 6.92 (d, J = 9.02 Hz, 2 H) 7.53 (d, J =9.02 Hz, 2 H) 8.36 (s, 1 H) 8.94 (t, J = 5.85 Hz, 1 H) 9.28 (s, 1 H)B10-X00-M03(C01)-D30 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s, 6 H) 2.28(s, 3 H) 2.47-2.59 (m, 4 H) 2.69 (s, 2 H) 3.02- 3.16 (m, 4 H) 3.83 (d, J= 5.73 Hz, 2 H) 4.34 (s, 3 H) 6.92 (d, J = 9.15 Hz, 2 H) 7.08 (s, 1 H)7.36 (s, 1 H) 7.53 (d, J = 9.02 Hz, 2 H) 8.12 (t, J = 5.67 Hz, 1 H) 8.35(s, 1 H) 9.27 (s, 1 H) B10-X00-M03(C01)-D162 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.33 (s, 6 H) trihydrochloride salt 2.70 (s, 2 H) 2.85 (d, J = 4.63Hz, 3 H) 2.95-3.05 (m, 2 H) 3.11-3.25 (m, 2 H) 3.52 (d, J = 11.46 Hz, 2H) 3.67 (s, 3 H) 3.74 (d, J = 13.66 Hz, 2 H) 4.00 (d, J = 5.97 Hz, 2 H)4.34 (s, 3 H) 6.99 (d, J = 9.15 Hz, 2 H) 7.60 (d, J = 9.02 Hz, 2 H) 8.37(s, 1 H) 8.54 (t, J = 6.04 Hz, 1 H) 9.39 (s, 1 H) 10.23 (s, 1 H)B10-X00-M03(C01)-D20 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (s, 6 H) 2.27(s, 3 H) 2.50-2.57 (m, 4 H) 2.71 (s, 2 H) 3.07- 3.13 (m, 4 H) 4.38 (s, 3H) 6.92 (d, J = 9.15 Hz, 2 H) 7.06-7.15 (m, 1 H) 7.31-7.40 (m, 2 H) 7.55(d, J = 9.15 Hz, 2 H) 7.80 (dd, J = 8.54, 0.98 Hz, 2 H) 8.37 (s, 1 H)9.29 (s, 1 H) 10.29 (s, 1 H) B10-X00-M03(C01)-D09 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33 (s, 6 H) 2.70 (s, 2 H) 2.84 (d, J = 4.15 Hz, 3 H)3.03 (t, J = 12.56 Hz, 2 H) 3.10-3.25 (m, 2 H) 3.36-3.55 (m, 2 H) 3.74(d, J = 13.05 Hz, 2 H) 4.32 (s, 3 H) 4.45 (d, J = 6.34 Hz, 2 H) 7.00 (d,J = 9.02 Hz, 2 H) 7.21-7.29 (m, 1 H) 7.31-7.36 (m, 4 H) 7.59 (d, J =9.02 Hz, 2 H) 8.36 (s, 1 H) 8.77 (t, J = 6.34 Hz, 1 H) 9.46 (s, 1 H)10.46 (s, 1 H) B10-X00-M03(C01)-D34 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23(s, 3 H) 1.33 (s, 3 H) 2.27 (s, 3 H) 2.48-2.56 (m, 4 H) 2.67 (s, 2 H)3.04-3.14 (m, 4 H) 3.71 (t, J = 6.04 Hz, 2 H) 4.35 (s, 3 H) 4.96 (t, J =5.61 Hz, 1 H) 5.02 (dt, J = 7.83, 6.20 Hz, 1 H) 6.92 (d, J = 9.15 Hz, 2H) 7.22-7.28 (m, 1 H) 7.34 (t, J = 7.44 Hz, 2 H) 7.38-7.42 (m, 2 H) 7.53(d, J = 9.15 Hz, 2 H) 8.34 (s, 1 H) 8.42 (d, J = 8.17 Hz, 1 H) 9.26 (s,1 H) B10-X00-M03(C01)-D70 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (s, 3 H)1.36 (s, 3 H) 2.27 (s, 3 H) 2.45-2.54 (m, 4 H) 2.61- 2.72 (m, 2 H)3.073.12 (m, 4 H) 3.61-3.68 (m, J = 12.44, 5.12 Hz, 1 H) 3.80 (dd, J =12.44, 9.51 Hz, 1 H) 4.35 (s, 3 H) 5.27 (td, J = 9.21, 5.00 Hz, 1 H)6.92 (d, J = 9.15 Hz, 2 H) 7.27-7.33 (m, 1 H) 7.38 (t, J = 7.44 Hz, 2 H)7.48 (d, J = 7.07 Hz, 2 H) 7.53 (d, J = 9.02 Hz, 2 H) 8.34 (s, 1 H) 8.93(d, J = 9.02 Hz, 1 H) 9.27 (s, 1 H) B10-X00-M03(C01)-D163 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.08 (d, J = 6.54 Hz, 3 H) 1.31 (s, 6 H) 2.17 (s, 6H) 2.22 (s, 3 H) 2.45 (m, 6 H) 2.65 (s, 2 H) 3.04 (m, 4 H) 4.04 (m, 1 H)4.29 (s, 3 H) 6.90 (d, J = 9.02 Hz, 2 H) 7.49 (d, J = 9.02 Hz, 2 H) 7.91(d, J = 8.46 Hz, 1 H) 8.32 (s, 1 H) 9.27 (s, 1 H) B10-X00-M02(C01)-D04¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (s, 6 H) 2.26 (s, 3 H) 2.47 (m, 4H) 2.93 (s, 2 H) 3.09 (m, 4 H) 4.33 (s, 3 H) 6.93 (d, J = 9.32 Hz, 2 H)7.25 (s, 1 H) 7.46 (s, 1 H) 7.53 (d, J = 9.32 Hz, 2 H) 8.44 (s, 1 H)9.28 (s, 1 H)

Reported below are the analytical HPLC/Mass data for some representativecompounds of the invention.

TABLE XVIII M + H Time 1 Method B10-X00-M03(C01)-D136 560.34 2.2 1B10-X00-M03(C01)-D26 532.34 2.25 1 B10-X00-M03(C01)-D86 518.33 2.43 1B10-X00-M03(C01)-D137 534.32 2.34 1 B10-X00-M03(C01)-D116 558.36 2.45 1B10-X00-M03(C01)-D79 535.31 2.5 1 B10-X00-M03(C01)-D123 517.3 2.67 1B10-X00-M03(C01)-D135 517.3 2.64 1 B10-X00-M03(C01)-D138 505.3 2.63 1B10-X00-M03(C01)-D139 506.29 2.45 1 B10-X00-M03(C01)-D95 521.29 2.77 1B10-X00-M03(C01)-D119 521.29 2.77 1 B10-X00-M03(C01)-D81 558.36 2.6 1B10-X00-M03(C01)-D115 544.34 2.45 1 B10-X00-M03(C01)-D105 531.31 2.9 1B10-X00-M03(C01)-D140 545.33 2.87 1 B10-X00-M03(C01)-D100 545.33 3.05 1B10-X00-M03(C01)-D82 505.3 3.1 1 B10-X00-M03(C01)-D97 505.3 3.19 1B10-X00-M03(C01)-D121 572.34 3.23 1 B10-X00-M03(C01)-D06 491.28 2.93 1B10-X00-M03(C01)-D104 505.3 3.21 1 B10-X00-M03(C01)-D113 531.31 3.07 1B10-X00-M03(C01)-D83 549.29 3.45 1 B10-X00-M03(C01)-D131 519.31 3.47 1B10-X00-M03(C01)-D102 475.29 3.54 1 B10-X00-M03(C01)-D122 545.33 3.32 1B10-X00-M03(C01)-D85 506.29 3.24 3 B10-X00-M03(C01)-D93 559.34 3.61 1B10-X00-M03(C01)-D94 493.28 3.58 1 B10-X00-M03(C01)-D60 567.31 3.92 1B10-X00-M03(C01)-D117 533.33 3.77 1 B10-X00-M03(C01)-D34 567.31 3.99 1B10-X00-M03(C01)-D87 567.31 4.21 1 B10-X00-M03(C01)-D108 634.35 4.07 1B10-X00-M03(C01)-D91 533.29 4.01 1 B10-X00-M03(C01)-D114 602.35 4.1 1B10-X00-M03(C01)-D14 515.32 4.64 1 B10-X00-M03(C01)-D141 552.31 4.34 1B10-X00-M03(C01)-D109 580.34 4.89 1 B10-X00-M03(C01)-D107 531.28 3.56 1

Example 598-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide tri-hydrochloride salt [B10-X00-M03(C01)-D04]

To8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide (7.00 g, 15.192 mmol) dissolved into a 1:1 mixture ofmethanol/dichloromethane (149 mL) 4M hydrochloric acid in dioxane (12.12mL, 48.48 mL) was added and the solution stirred at room temperature for2 hours. After removing the solvent under reduced pressure, the reddishsolid was dried at 43° C. under vacuum for 10 hours. There were obtained8.11 g of the title compound as a red solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 6H) 2.69 (s, 2H) 2.76 (d,J=4.76 Hz, 3H) 2.85 (d, J=3.54 Hz, 3H) 2.95-3.08 (m, 2H) 3.10-3.26 (m,2H) 3.39-3.55 (m, 2H) 3.74 (d, J=13.41 Hz, 2H) 4.30 (s, 3H) 7.00 (d,J=9.02 Hz, 2H) 7.59 (d, J=8.90 Hz, 2H) 8.16 (q, J=4.51 Hz, 1H) 8.36 (s,1H) 9.44 (s, 1H) 10.37 (s, 1H)

Example 60

8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide[B10-X00-M03(C01)-D03]

To a suspension of8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid potassium salt (185.5 mg, 0.382 mmol) in a 1:1 mixture of anhydroustetrahydrofurane and dimethylformamide (4.8 mL), N-ethyldiisopropylamine(0.13 mL, 0.760 mmol), 1-hydroxybenzotriazole ammonium salt (102 mg,0.760 mmol) were added in that order. The reaction mixture was cooled to0° C., treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC)(146 mg, 0.760 mmol) and then stirred at room temperature for 18 hours.

The reaction mixture was poured into water (10 mL) and the precipitatewas filtered, washed with water, dried under vacuum at 40° C. for 4hours. There were obtained 130 mg (yield 76%) of pure title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 6H) 2.26 (s, 3H) 2.46-2.56 (m,4H) 2.68 (s, 2H) 3.04-3.14 (m, 4H) 4.31 (s, 3H) 6.91 (d, J=9.15 Hz, 2H)7.29 (s, 1H) 7.53 (d, J=9.15 Hz, 2H) 7.55 (s, 1H) 8.34 (s, 1H) 9.25 (s,1H)

By working according to the above method the following compounds wereprepared:

TABLE XIX B04-X00-M03(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s,6 H) 2.71 (s, 2 H) 4.33 (s, 3 H) 6.97 (tt, J 7.38, 1.10 Hz, 1 H) 7.31(m, 3 H) 7.56 (s, 1 H) 7.71 (dd, J 8.60, 1.04 Hz, 2 H) 8.41 (s, 1 H)9.52 (s, 1 H) B12-X00-M03(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35(s, 6 H) 2.72 (s, 2 H) 2.87 (d, J 4.63 Hz, 3 H) 3.35 (m, 8 H) 4.34 (s, 3H) 7.21 (d, J 8.78 Hz, 1 H) 7.32 (s, 1 H) 7.56 (s, 1 H) 7.59 (dd, J8.78, 2.56 Hz, 1 H) 8.01 (d, J 2.44 Hz, 1 H) 8.43 (s, 1 H) 9.68 (s, 1 H)10.39 (s, 1 H) B13-X00-M03(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35(s, 6 H) 2.73 (s, 2 H) 2.88 (d, J 4.63 Hz, 3 H) 3.32 (m, 8 H) 4.32 (s, 3H) 7.33 (s, 1 H) 7.54 (d, J 8.90 Hz, 1 H) 7.56 (s, 1 H) 8.01 (dd, J8.72, 2.38 Hz, 1 H) 8.12 (d, J 2.56 Hz, 1 H) 8.45 (s, 1 H) 9.86 (s, 1 H)10.35 (s, 1 H) B19-X00-M03(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34(s, 6 H) 2.68 (s, 2 H) 3.00-3.13 (m, 4 H) 3.70-3.80 (m, 4 H) 4.31 (s, 3H) 6.92 (d, J = 9.02 Hz, 2 H) 7.29 (s, 1 H) 7.51-7.59 (m, 3 H) 8.34 (s,1 H) 9.27 (s, 1 H) B13-X00-M02(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.29 (m, 6 H) 2.86 (d, J 4.39 Hz, 3 H) 2.95 (s, 2 H) 3.34 (m, 8 H) 4.37(s, 3 H) 7.21 (d, J 8.78 Hz, 1 H) 7.29 (s, 1 H) 7.45 (s, 1 H) 7.58 (dd,J 8.84, 2.50 Hz, 1 H) 8.04 (d, J 2.44 Hz, 1 H) 8.53 (s, 1 H) 9.71 (s, 1H) 10.49 (s, 1 H) B12-X00-M02(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32 (m, 6 H) 2.88 (d, J 4.39 Hz, 3 H) 2.96 (s, 2 H) 3.38 (m, 8 H) 4.35(s, 3 H) 7.29 (s, 1 H) 7.46 (s, 1 H) 7.54 (d, J 8.90 Hz, 1 H) 8.00 (dd,J 8.66, 2.32 Hz, 1 H) 8.15 (d, J 2.44 Hz, 1 H) 8.55 (s, 1 H) 9.89 (s, 1H) 10.32 (s, 1 H) B04-X00-M02(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.30 (s, 6 H) 2.95 (s, 2 H) 4.35 (s, 3 H) 6.98 (tt, J 7.35, 1.04, 0.98Hz, 1 H) 7.27 (s, 1 H) 7.31 (dd, J 8.35, 7.50 Hz, 2 H) 7.47 (s, 1 H)7.72 (dd, J 8.54, 0.98 Hz, 2 H) 8.51 (s, 1 H) 9.55 (s, 1 H)B10-X00-M02(C01)-D03 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (s, 6 H) 2.26(s, 3 H) 2.47 (m, 4 H) 2.93 (s, 2 H) 3.09 (m, 4 H) 4.33 (s, 3 H) 6.93(d, J = 9.32 Hz, 2 H) 7.25 (s, 1 H) 7.46 (s, 1 H) 7.53 (d, J = 9.32 Hz,2 H) 8.44 (s, 1 H) 9.28 (s, 1 H)

Example 61

Step 1.8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid potassium salt [B00-X00-M03(C01)-D02]

A suspension of ethyl8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate(20.00 g, 66.368 mmol) in anhydrous ethanol (250 mL), 1.5M potassiumhydroxide in ethanol (150 mL) was added under good stirring and themixture was heated to reflux for 1.5 hours. After cooling in an icebath, a solid was formed; that was filtered washing with ethanol, driedat 40° C. under vacuum to yield 17.34 g (yield 84%) of white solidcompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (s, 6H) 2.51 (s, 2H) 4.16 (s, 3H)6.37 (s, 2H) 8.07 (s, 1H)

Step 2.8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide [B00-X00-M03(C01)-D04]

To a suspension of8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid potassium salt (17.00 g, 54.594 mmol) in a 1:1 mixture of anhydroustetrahydrofurane and dimethylformamide (340 mL), 2 M methylamine intetrahydrofurane (40.80 mL, 81.60 mmol), 1-hydroxybenzotriazole (8.840g, 65.418 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC)(12.540 g, 65.418 mmol) were added in that order, and the thick slurrywas stirred at room temperature for 20 hours.

The reaction mixture was poured into water (2.5 L) and extracted withdichloromethane (4×250 mL) The combined organic extracts were washedwith water (50 mL), dried over anhydrous sodium sulphate, and thesolvent was removed under reduced pressure. There were obtained 17.0 gof yellowish solid that were triturated with diethylether to yield 13.05g (yield 87%) of the desired compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (s, 6H) 2.60 (s, 2H) 2.75 (d,J=4.76 Hz, 3H) 4.30 (s, 3H) 6.55 (s, 2H) 8.12 (q, J=4.39 Hz, 1H) 8.17(s, 1H).

By working in an analogous way the following compounds were prepared:

-   8-amino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid    methylamide [B00-X00-M00(C01)-D04]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.69-2.74 (m, 2H) 2.74 (d, J=4.76 Hz,3H) 2.94 (t, J=7.56 Hz, 2H) 4.31 (s, 3H) 6.54 (s, 2H) 7.99-8.08 (m, 1H)8.18 (s, 1H);

-   8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide    [B00-X00-M03(C01)-D03]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (s, 6H) 2.61 (s, 2H) 4.30 (s, 3H)6.57 (s, 2H) 7.27 (s, 1H) 7.51 (s, 1H) 8.17 (s, 1H)

Step 3.8-iodo-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide

In a round bottom flask maintained under argon atmosphere, ethyl8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide (13.00 g, 45.400 mmol) was dissolved into anhydrousdimethoxyethane (800 mL); cesium iodide (11.795 g, 45.400 mmol),bisublimated iodine (5.761 g, 22.698 mmol), copper(I) iodide (2.594 g,13.621 mmol), and iso-amyl nitrite (9.107 mL, 68.100 mmol) were added inthat order and the mixture was heated to 70° C. for 22 hours.

After cooling to room temperature, the solids materials were removed bysuction filtration, washing with dichloromethane. The filtrate wasconcentrated to 400 mL, diluted with dichloromethane (1000 mL), washedwith 30% ammonium hydroxide (100 mL), 5% sodium thiosulphate (50 mL),water (4×100 mL), and dried over anhydrous sodium sulphate. The solventwas removed under vacuum to afford 11.00 g of dark oil that wastriturated with diethylether to yield 4.300 g of the title compound as ayellow solid. Purification of the mother liquors by flash chromatographyon silica gel (eluant dichloromethane/methanol 97:3) afforded further2.04 g of yellowish solid compound (overall yield 35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 6H) 2.76 (d, J=4.76 Hz, 3H)2.80 (s, 2H) 4.24 (s, 3H) 8.16-8.25 (m, 1H) 8.48 (s, 1H)

Step 4.8-[3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-114-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide [B104-X00-M03(C01)-D04]

Pd(OAc)₂ (16.34 mg, 0.0728 mmol), (±)-BINAP (45.33 mg, 0.0728 mmol) anddimethylformamide (12 mL) were charged in a round-bottom flask flushedwith argon. The mixture was stirred under argon for 30 minutes. Then3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (448.4 mg, 2.184 mmol),ethyl8-iodo-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylicacid methylamide (300 mg, 0.728 mmol), K₂CO₃ (1.508 g, 10.910 mmol) anddimethylformamide (10 mL) were added. The resulting mixture was heatedto 80° C. in an oil bath under argon with good stirring for 3 hours.

After cooling to room temperature, the reaction mixture was filtered bysuction filtration washing with dichloromethane and the filtrate wasevaporated to dryness. The crude was purified by flash chromatography onsilica gel (eluant: dichloromethane/methanol 95:5) to afford 215 mg(yield 62%) of pure title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s, 6H) 2.25 (s, 3H) 2.42 (m, 4H)2.71 (s, 2H) 2.77 (d, J=4.76 Hz, 3H) 3.44 (m, 4H) 3.48 (s, 2H) 4.35 (s,3H) 6.91 (d, J=7.31 Hz, 1H) 7.26 (t, J=7.68 Hz, 1H) 7.56 (d, J=8.78 Hz,1H) 7.76 (s, 1H) 8.15 (s, 1H) 8.41 (s, 1H) 9.5 (s, 1H)

By working according to the above method the following compounds wereprepared:

TABLE XX B10-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 6H) 2.26 (s, 3 H) 2.44-2.54 (m, 4 H) 2.68 (s, 2 H) 2.76 (d, J = 4.76 Hz,3 H) 3.04-3.13 (m, 4 H) 4.31 (s, 3 H) 6.91 (d, J = 9.02 Hz, 2 H) 7.53(d, J = 9.02 Hz, 2 H) 8.15 (q, J = 4.84 Hz, 1 H) 8.34 (s, 1 H) 9.25 (s,1 H) B09-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 6 H)2.27 (s, 3 H) 2.52 (m, 4 H) 2.70 (s, 2 H) 2.76 (d, J = 4.76 Hz, 3 H)3.13 (m, 4 H) 4.33 (s, 3 H) 6.59 (d, J = 7.31 Hz, 1 H) 7.14 (t, J = 7.68Hz, 1 H) 7.23 (s, 1 H) 7.26 (d, J = 8.78 Hz, 1 H) 8.15 (s, 1 H) 8.39 (s,1 H) 9.33 (s, 1 H) B101-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34 (s, 6 H) 2.55-3.62 (m, 13 H) 2.71 (s, 2 H) 2.75-2.79 (m, J = 4.76Hz, 3 H) 4.33 (s, 3 H) 7.25 (d, J = 10.24 Hz, 2 H) 7.69 (d, J = 7.80 Hz,2 H) 8.10-8.18 (m, 1 H) 8.41 (s, 1 H) 9.55 (s, 1 H) B19-X00-M03(C01)-D04¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 6 H) 2.68 (s, 2 H) 2.76 (d, J =4.76 Hz, 3 H) 3.02-3.09 (m, 4 H) 3.72-3.79 (m, 4 H) 4.31 (s, 3 H) 6.93(d, J = 9.02 Hz, 2 H) 7.55 (d, J = 9.02 Hz, 2 H) 8.15 (q, J = 4.63 Hz, 1H) 8.34 (s, 1 H) 9.28 (s, 1 H) B107-X00-M03(C01)-D04 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.34 (s, 6 H) 2.70 (s, 2 H) 2.76 (d, J = 4.76 Hz, 3 H)3.06-3.13 (m, 4 H) 3.73-3.78 (m, 4 H) 4.33 (s, 3 H) 6.59 (dd, J = 7.93,2.07 Hz, 1 H) 7.16 (t, J = 8.11 Hz, 1 H) 7.23 (t, J = 2.01 Hz, 1 H) 7.30(dd, J = 7.74, 1.40 Hz, 1 H) 8.16 (q, J = 4.59 Hz, 1 H) 8.39 (s, 1 H)9.35 (s, 1 H) B102-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34(s, 6 H) 2.35 (s, 4 H) 2.70 (s, 2 H) 2.76 (d, J = 4.76 Hz, 3 H) 3.43 (s,2 H) 3.58 (s, 4 H) 4.33 (s, 3 H) 7.25 (s, 2 H) 7.66 (s, 2 H) 8.40 (s, 1H) 9.51 (s, 1 H) B105-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.35 (s, 7 H) 2.38 (s, 4 H) 2.71 (s, 2 H) 2.77 (d, J = 4.76 Hz, 3 H)3.44 (s, 2 H) 3.58 (s, 5 H) 4.36 (s, 3 H) 6.87-6.99 (m, 1 H) 7.25 (t, J= 7.56 Hz, 1 H) 7.58 (d, J = 6.71 Hz, 1 H) 7.76 (s, 1 H) 8.41 (s, 1 H)B103-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 6 H)1.64-2.07 (m, 4 H) 2.37-2.62 (m, 5 H) 2.68 (s, 2 H) 2.76 (d, J = 4.63Hz, 3 H) 2.81-3.00 (m, 2 H) 4.30 (s, 3 H) 4.34-4.46 (m, 1 H) 6.94 (d, J= 9.02 Hz, 2 H) 7.58 (d, J = 9.02 Hz, 2 H) 8.15 (q, J = 4.55 Hz, 1 H)8.36 (s, 1 H) 9.34 (s, 1 H) B106-X00-M03(C01)-D04 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.34 (s, 6 H) 1.70-2.18 (m, 4 H) 2.59 (s, 3 H) 2.71 (s, 2H) 2.77 (d, J = 4.76 Hz, 3 H) 2.93-3.50 (m, 4 H) 4.35 (s, 3 H) 4.40-4.57 (m, 1 H) 6.61 (dd, J = 7.93, 2.07 Hz, 1 H) 7.21 (t, J = 8.11 Hz, 1H) 7.26-7.32 (m, 1 H) 7.47 (s, 1 H) 8.12- 8.19 (m, 1 H) 8.42 (s, 1 H)9.51 (s, 1 H) B120-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.04-1.24 (m, 6 H) 1.33 (s, 6 H) 2.68 (s, 2 H) 2.76 (d, J = 4.76 Hz, 3H) 2.79-3.52 (m, 9 H) 4.31 (s, 3 H) 6.94 (d, J = 8.78 Hz, 2 H) 7.55 (d,J = 8.78 Hz, 2 H) 8.15 (q, J = 4.63 Hz, 1 H) 8.34 (s, 1 H) 9.28 (s, 1 H)B173-X00-M03(C01)-D04 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (s, 6 H)2.40-2.50 (m, 4 H) 2.68 (s, 2 H) 2.74 (d, J = 4.76 Hz, 3 H) 3.53 (s, 2H) 3.60 (m, 4 H) 4.30 (s, 3 H) 6.98 (d, 1 H) 7.06 (dd, 1 H) 7.23 (d, 1H) 8.14 (q, 1 H) 8.37 (s, 1 H) 9.39 (s, 1 H) 10 (bs, 1H)

Reported below are the analytical HPLC/Mass data for some representativecompounds of the invention

TABLE XXI M + H RT method B121-X00-M03(C01)-D04 442.514 4.40 1B122-X00-M03(C01)-D04 393.461 4.70 1 B123-X00-M03(C01)-D04 380.422 3.421 B124-X00-M03(C01)-D04 379.434 4.86 1 B125-X00-M03(C01)-D04 406.5035.60 1 B126-X00-M03(C01)-D04 395.433 4.37 1 B127-X00-M03(C01)-D04442.514 4.90 1 B128-X00-M03(C01)-D04 406.46 5.40 1 B114-X00-M03(C01)-D04393.461 4.35 1 B129-X00-M03(C01)-D04 406.46 4.10 1 B11-X00-M03(C01)-D04393.461 4.50 1 B130-X00-M03(C01)-D04 406.46 4.10 1 B131-X00-M03(C01)-D04449.524 6.10 1 B168-X00-M03(C01)-D04 420.487 4.50 1B132-X00-M03(C01)-D04 448.54 6.14 1 B133-X00-M03(C01)-D04 412.488 4.90 1B134-X00-M03(C01)-D04 407.487 4.90 1 B135-X00-M03(C01)-D04 406.46 4.80 1B21-X00-M03(C01)-D04 429.498 4.66 1 B136-X00-M03(C01)-D04 439.489 4.76 1B137-X00-M03(C01)-D04 409.46 4.7 1 B138-X00-M03(C01)-D04 393.461 5.02 1B139-X00-M03(C01)-D04 407.487 4.77 1 B140-X00-M03(C01)-D04 393.46 4.62 1B141-X00-M03(C01)-D04 407.487 4.60 1 B142-X00-M03(C01)-D04 395.433 4.051 B143-X00-M03(C01)-D04 406.503 6.10 1 B144-X00-M03(C01)-D04 446.5686.27 1 B145-X00-M03(C01)-D04 420.53 3.41 1 B17-X00-M03(C01)-D04 434.5575.27 1 B146-X00-M03(C01)-D04 488.648 4.6 1 B147-X00-M03(C01)-D04 420.533.58 1 B148-X00-M03(C01)-D04 407.487 4.33 1 B149-X00-M03(C01)-D04407.487 4.50 1 B150-X00-M03(C01)-D04 492.549 3.85 1B151-X00-M03(C01)-D04 486.566 5.38 1 B152-X00-M03(C01)-D04 510.632 6.601 B153-X00-M03(C01)-D04 512.604 5.55 1 B154-X00-M03(C01)-D04 506.5765.34 1 B155-X00-M03(C01)-D04 504.604 5.03 1 B156-X00-M03(C01)-D04489.593 4.45 1 B13-X00-M03(C01)-D04 496.028 4.28 1 B117-X00-M03(C01)-D04540.479 4.38 1 B157-X00-M03(C01)-D04 512.604 5.60 1B158-X00-M03(C01)-D04 466.53 5.73 1 B159-X00-M03(C01)-D04 510.632 4.94 1B160-X00-M03(C01)-D04 491.609 3.71 1 B161-X00-M03(C01)-D04 490.577 5.411 B162-X00-M03(C01)-D04 448.584 3.95 1 B163-X00-M03(C01)-D04 476.5943.82 1 B164-X00-M03(C01)-D04 434.557 3.69 1 B165-X00-M03(C01)-D04436.486 4.44 1 B109-X00-M03(C01)-D04 479.573 3.93 1B166-X00-M03(C01)-D04 483.545 5.07 1 B12-X00-M03(C01)-D04 529.58 4.66 1B167-X00-M03(C01)-D04 505.635 3.75 1

Example 62

Step. 1 Loading Primary Amines to a Solid Support (Resin) A: Case wherethe “resin” is 4-(4-formyl-3-methoxyphenoxy)butyryl polyethylene glycolgrafted aminomethylpolystyrene-1% DVB

For each variant of R2 primary amine, 1 gram (0.39 mmol) of theaforementioned resin was charged to a 10 mL Argonaut Quest 210 reactiontube. Trimethyl orthoformate (7 mL) was added to the tube along with 5equivalents (1.95 mmol) of each primary amine (indicated as R2 in thescheme). The reaction was mixed on the Quest at 25° C. for 16 hoursfollowed by a 2-hour period of heating at 70° C. After cooling andremoval of the reaction solution, the resin was washed once withtrimethyl orthoformate (7 mL each) and three times with anhydrousmethanol (7 mL). Anhydrous methanol (5 mL) was then added to the resin,followed by the addition of 148 mg (3.9 mmol, 10 equiv) of sodiumborohydride. After vigorous gas evolution had ceased, the tube wascapped and mixed for 8 hours at room temperature. The resin was washed 3times with methanol (5 mL), three times with methanol/water (1:1, 5 mL),and three times with DMF (5 mL). The resin was then treated with 20%piperidine in DMF for 1 hour at room temperature. Again, the resin waswashed three times with DMF (5 mL), three times with methanol (5 mL),and three times with dichloromethane (5 mL) A sample of the resin wastested for quantitative amine loading by using the Fmoc UV-spectrometricmethod described below. Qualitatively, the resin was analyzed using thechloranil test method described below.

B: Case where the “Resin” is Rink Amide,4-(2′,4′-dimethoxyphenyl-fmoc-aminomethyl)phenoxy (copolystyrene-1% DVB)

1 g (0.39 mmol) of the aforementioned resin were charged into a 10 mLArgonaut Quest 210 reaction tube. The resin was treated with 20%piperidine in DMF for 5 minutes and a then a second treatment occurredfor 30 minutes at room temperature. The resin was washed with DMF (3×5mL), with methanol (3×5 mL) and with dichloromethane (3×5 mL)

Quantitative amine loading by using the Fmoc UV-spectrometric method:

A precisely tarred quantity (25 mg±5 mg) of dry, loaded resin wascharged into a 3 mL polypropylene syringe, fitted with a filter disk. Tothe syringe, 3 equivalents of 9-fluorenylmethyl chloroformate dissolvedin 1 mL of dichloromethane were charged and 1.5 equivalents ofN,N-diisopropylethylamine were then added. The resin was shaken by meansof orbital shaker, for 1 hour. The resin was washed with DMF (3×2 mL, 5min.), with methanol (3×2 mL, 5 min.), and with DCM (3×2 mL, 5 min.).

1 mL of a 20% piperidine solution in DMF was drawn from the syringe andagitated for 5 minutes at room temperature. The solution was dispensedinto a 10 mL volumetric flask. A second aliquot of the 20% piperidinesolution in DMF was drawn and agitated for 30 minutes at roomtemperature. Again, the solution was dispensed into the same 10 mLvolumetric flask (stock solution). DMF was added to the volumetric flaskto achieve a 10 mL total volume. This volumetric flask containing thestock solution was agitated thoroughly and exactly 0.5 mL weretransferred into a second 10 mL volumetric flask (test solution). Again,DMF was added to the volumetric flask up to a 10 mL total volume. Theabsorbance of this test solution was measured through an AmerashamPharmacia Biotech Ultrospec 3000 Pro, UV-Vis spectrometer at λ=302 nmagainst DMF as the blank. The post reaction resin substitution wascalculated using the following formula:loading(mmol/g)=(A ₃₀₂×20fold×10 mL)/8100×wtwhere A₃₀₂ is the UV absorbance at λ=302 nm, ε=8100 is the extinctioncoefficient of the piperidine-fluorenone adduct and wt is the tare ofthe resin in milligrams.

Qualitative chloranil (3,4,5,6-tetrachloro-1,2-benzoquinone) test forresin bound secondary amines: A small aliquot of pre-washed resincontaining the attached amine was placed in a micro-test tube. The beadswere washed once with acetone and the solvent was removed bydecantation. One drop of the chloranil test solution was added to thetest tube and allowed to stand at room temperature for 5 minutes. A darkgreen to brown color was a positive indication of a secondary amine. Theintensity of the color was a non-quantitative indication of secondaryamine concentration.

Test solution: a saturated solution of3,4,5,6-tetrachloro-1,2-benzoquinone in toluene at room temperature.

Step. 2 Acylation of the solid supported amine with8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carbonylfluoride

For each variant of R2 primary amine loaded onto 1 g (0.39 mmol) of theresin in step 1 above, the following pre-activated carboxylic acidfluoride reagent was added. In 5 mL of dichloromethane, 166 mg (0.47mmol, 1.2 equivalents) of8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate,155 mg (0.585 mmol, 1.5 equivalents) of tetramethylfluoroformamidiniumhexafluorophosphate and 0.102 mL (0.585 mmol, 1.5 equivalents) ofN,N-diisopropylethylamine were dissolved. N,N-Dimethylacetamide wasadded dropwise to the solution until all reagents were in solution withsonication. The reaction system was stirred at room temperature for 30minutes. Additional 0.102 mL (0.585 mmol, 1.5 equivalents) ofN,N-diisopropylethylamine were added to the solution, in 30 minutes, andthe entire content was charged to the resin on the Quest 210synthesizer. The resin was mixed for 18 hours at room temperature. Theresin was drained of the acylation cocktail and washed with DMF (3×5 mL,5 min.), with methanol (3×5 mL, 5 min.) and with DCM (3×5 mL, 5 min.).The resin was dried from DCM under vacuum. The resin was qualitativelytested for the acylation reaction completion using the chloranil testmethod. A sample of each dried resin was subjected to the quantitativeFmoc UV-spectrometric analysis to determine the extent of resin boundacylation.

Step. 3 Catalytic amination of the solid supported8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

Using a 4 mL Argonaut Trident synthesizer cassette, 200 mg (0.078 mmol)of each resin type from step 2 above, were charged into separate vials.To each of the reactor vials flushed with argon, potassium carbonate(0.158 g, 1.56 mmol), palladium acetate [Pd(OAc)₂] (1.8 mg, 0.008 mmol,10%), (±)-BINAP (5.0 mg, 0.008 mmol, 10%) and the corresponding R1 amine(0.156 mmol, 2 equivalents) in dimethyacetamide (2 mL) were added. Theresulting mixture was agitated at room temperature for 1 hour and thenheated to 60° C. for 16 hours on the Argonaut Trident External AgitationThermal Unit (EATU) synthesis station.

The resin was drained from the synthesis cocktail and washed using theArgonaut Trident EATU synthesis station with DMF (1×2 mL, 5 min.), withwater (1×2 mL, 5 min.), with DMF/water (1:1) (3×2 mL, 5 min.), with DMF(3×2 mL, 5 min.), with methanol (3×2 mL, 5 min.) and with DCM (3×2 mL, 5min.)

Step. 4 Cleavage of the Differentially Substituted8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamidefrom the Solid Support

To each Argonaut Trident reactor vial, 2 mL of the following resincleavage cocktail were added: dichloromethane (50 mL), trifluoroaceticacid (49 mL) and water (1 mL). The resin suspended in the cleavagecocktail was shaken for 1 hour at room temperature on the ArgonautTrident EATU synthesis station. The solution containing the crudeproducts was captured into separate vials where three additional resinwashing with dichloromethane (2 mL each) were also captured to the samecorresponding vials.

Example 63 N-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]guanidineStep 1. 1,3-bis(tert-butoxycarbonyl)guanidine

15 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.052mol) were suspended in 150 mL of gaseous ammonia in methanol and themixture was stirred at room temperature in a close bottle at roomtemperature. The resulting solution was concentrated in vacuo until 10 g(74% yield) of the title compound precipitated which were collected byfiltration.

Step 2. 1,3-bis(tert-butoxycarbonyl)-2-trifluoromethanesulfonylguanidine

A solution of 5.2 g (20 mmol) of 1,3-bis(tert-butoxycarbonyl)guanidinein 100 mL of dry dichloromethane was cooled to −78° C. under stirringand 5.6 g (20 mmol) of trifluoromethanesulfonic anhydride were addeddropwise. The reaction mixture was allowed to come to room temperatureand stirred for 5 hours. An aqueous solution of NaHSO₄ was added and theorganic layer dried over Na₂SO₄ and evaporated to dryness. The residuewas purified by chromatography on a silica gel column (eluant petroleumether/ethyl acetate 7/3) to give 4.0 g (51% yield) of the titlecompound.

Step 3. N-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]guanidine

To a solution of 3.0 g (13.3 mmol) of4-(3-chloro-4-methylpiperazin-1-yl)aniline and 2.22 mL (16.0 mmol) oftriethylamine in 36 mL of dichloromethane, 6.0 g (15.3 mmol) of1,3-bis(tert-butoxycarbonyl)-2-trifluoromethanesulfonylguanidine wereadded. The reaction mixture was stirred at room temperature for 72hours. The solution was diluted with further dichloromethane, washedwith water and the solvent dried over Na₂SO₄ and evaporated in vacuo.The residue was purified by chromatography on a silica gel column(eluant dichloromethane/methanol 92/8) giving 5.4 g (86.2% yield) of aprotected intermediate, that was treated with 60 mL of 4 N HCl indioxane. The mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue redissolved inwater, the resulting solution neutralized and the product extracted withethyl acetate. The solvent was removed under reduced pressure to give2.4 g (78.7% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H) 2.48 (m, 4H) 2.90 (m, 4H)5.38 (bs, 4H) 6.72 (dd, J 2.44, 8.42 Hz, 1H) 6.82 (d, J 2.44, 1H) 7.01(d, J 8.42 Hz, 1H).

By working analogously, but employing the suitable substituted anilinederivative, the following compounds were prepared:

-   N-[3-(4-methylpiperazin-1-yl)phenyl]guanidine;-   N-[4-(4-methylpiperazin-1-yl)phenyl]guanidine;

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.80 (s, 3H) 7.09 (m. 4H) 7.41 (s, 2H)9.85 (s, 1H) 11.39 (s, 1H) (as dihydrochloride);

-   N-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]guanidine;

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (s, 3H) 2.43 (m, 4H) 2.80 (m, 4H)5.46 (bs, 4H) 7.02 (m, 2H) 7.37 (d, 1H, J 8.42 Hz);

-   N-(3-chlorophenyl)guanidine.

Example 64

Step 1. Tert-butyl (1S)-2-hydroxy-1-phenylethylcarbamate

A solution of 40 g (0.291 mol) of (2S)-2-amino-2-phenylethanol in 1250mL of ethylacetate and 99.83 mL (0.583 mol) ofN-ethyl-N,N-diisopropylamine was cooled to 0° C. and 76.21 g (0.349 mol)of di-tert-butyl dicarbonate were added portionwise. The mixture wasstirred at room temperature for 3 hours then it was washed with 400 mLof 1M KHSO₄. The organic layer was dried over Na₂SO₄ thus affording69.88 g of the title compound.

Step 2. (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethylmethanesulfonate

The solution of 68.9 g (0.29 mol) of tert-butyl(1S)-2-hydroxy-1-phenylethylcarbamate and triethylamine (40.36 mL, 0.29mol) in 700 mL of dry dichloromethane under inert atmosphere was cooledto −10° C. and 24.79 mL (0.319 mol) of mesylchloride were addeddropwise. After 2 hours at 0° C. the mixture was poured into ice andwater and extracted with dichloromethane. The organic phase was washedwith diluted HCl, aqueous NaHCO₃, brine and dried over Na₂SO₄ yielding89.8 g of the product (98% yield).

Step 3. Tert-butyl (1S)-2-morpholin-4-yl-1-phenylethylcarbamate

The mixture of 25 g (0.0792 mol) of(2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate andmorpholine (69.37 mL, 0.792 mol) in 250 mL of dry THF under inertatmosphere was refluxed for 8 hours. The reaction was then cooled toroom temperature, treated with diethylether and the solid filtered. Thesolution was evaporated affording the crude as a yellow oil that waspurified through silica gel chromatography (eluant hexane/ethylacetate6/4). 11.59 g of the title product were isolated (48% yield).

Step 4., (1S)-2-morpholin-4-yl-1-phenylethanamine dihydrochloride

A solution of 11.58 g (0.0378 mol) of tert-butyl(1S)-2-morpholin-4-yl-1-phenylethylcarbamate in 100 mL ofdichloromethane was treated with 120 mL of HCl 4M in dioxane and stirredfor 18 hours. The mixture was diluted with diethylether and the productfiltered (9.48 g, 90% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.37 (m, 6H) 3.83 (m, 4H) 4.90 (m, 1H)7.51 (m, 5H) 8.84 (bs, 3H).

By working analogously the following compounds was prepared:

-   (1S)-2-(4-methylpiperazin-1-yl)-1-phenylethanamine trihydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.78 (m, 13H) 4.47 (m, 1H) 7.46 (m, 5H)8.45 (bs, 3H) 10.40 (bs, 1H).

Example 65

Step. 1 1-tert-butyl-4-(4-nitrophenyl)piperazine

A solution of 800 mg (5.67 mmol) of 1-fluoro-4-nitrobenzene, 2.07 g (1.2mmol) of 1-tert-butylpiperazine dihydrobromide and 3.2 mL (20.41 mmol)of triethylamine, in 22 mL of acetonitrile, was refluxed for 10 hours.The mixture was cooled to room temperature, diluted with water andextracted with dichloromethane. The organic layer was washed with waterand brine, dried over Na₂SO₄ and evaporated. Purification by flashchromatography (eluant dichloromethane/methanol 7/3) yielded 860 mg ofthe title compound as yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (s, 9H) 2.63 (m, 4H) 3.43 (m, 4H)7.03 (d, 2H) 8.05 (d, 2H).

Step 2. 4-(4-tert-butylpiperazin-1-yl)phenylamine

To a solution of 840 mg (3.189 mmol) of1-tert-butyl-4-(4-nitrophenyl)piperazine in 24 mL of methanol, 904 mg(16.9 mmol) of ammonium chloride dissolved in 6 mL of water and 552 mg(9.886 mmol) of iron were added. After 7 hours, the suspension wascooled and filtered. pH was adjusted to 10 through portionwise additionof Na₂CO₃ to the aqueous phase. Extraction with dichloromethane yielded667 mg of the title amine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (s, 9H) 2.62 (m, 4H) 2.89 (m, 4H)4.52 (s, 2H) 6.50 (d, J=8.78 Hz, 2H) 6.67 (d, J=8.78 Hz, 2H).

Example 66

N-[3-(1-Methyl-piperidin-4-yloxy)-phenyl]acetamide

A suspension of N-(3-Hydroxy-phenyl)-acetamide (30.2 g) in anhydroustetrahydrofuran (600 mL) was treated with 4-hydroxy-N-methylpiperidine(30.54 mL) and triphenylphosphine (68.18 g); a solution ofdiethylazadicarboxylate in anhydrous tetrahydrofuran (THF) (40.94 mL in60 mL of THF) was added dropwise and the mixture was stirred at roomtemperature for 2 hours and then heated to 50° C. overnight.

Further amounts of triphenylphosphine (28.00 g) anddiethylazadicarboxylate (14 mL) were added and the heating was continuedfor additional 24 hours.

The solvent was removed under vacuum and the residue was taken up withethyl acetate (600 mL), and extracted with 2N hydrochloric acid (3×200mL). The aqueous layer was washed with ethyl acetate and pH was broughtto 10 by addition of 20% sodium hydroxide. Extraction with ethyl acetate(4×100 mL) was carried out and the combined organic extracts were washedwith brine and dried over anhydrous sodium sulphate. The solvent wasremoved under vacuum and the crude was purified by flash chromatographyon silica gel (eluant dichloromethane/methanol 85:15 then +0.1%triethylamine) to yield 21 g of the desired compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52-1.68 (m, 2H) 1.83-1.96 (m, 2H) 2.01(s, 3H) 2.14 (s, 3H) 2.46-2.52 (m, 2H) 2.52-2.63 (m, 2H) 4.18-4.20 (m,1H) 6.59 (d, 1H) 7.05 (d, 1H) 7.14 (t, 1H) 7.26 (s, 1H) 9.83 (s, 1H).

3-(1-Methyl-piperidin-4-yloxy)-phenylamine

A solution of N-[3-(1-Methyl-piperidin-4-yloxy)-phenyl]-acetamide (2.604g) in absolute ethanol (40 mL) was treated with 37% hydrochloric acidand the solution was heated to reflux for 3 hours.

After removing the solvent under vacuum, the residue was dissolved inwater and washed with ethyl acetate (30 mL). The aqueous solution wasbasified by 20% sodium hydroxide and extracted with ethyl acetate (4×50mL); the combined organic layers were washed with brine (4×20 mL), withwater (2×10 mL) and dried over anhydrous sodium sulphate. After removingthe solvent, the crude (2.00 g) was crystallized from n-hexane and ethylacetate to yield 1.00 g of pure compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.68 (m, 2H) 1.82-1.94 (m, 2H)2.12-2.27 (m, 2H) 2.21 (s, 3H) 2.58-2.71 (m, 2H) 4.14-4.29 (m, 1H) 4.98(s, 2H) 6.09 (ddd, J=8.11, 2.32, 0.79 Hz, 1H) 6.14 (ddd, J=7.83, 2.04,0.98 Hz, 1H) 6.16 (t, J=2.19 Hz, 1H) 6.88 (t, J=7.99 Hz, 1H)

Example 67 5-Amino-2-(4-methyl-piperazin-1-yl)-phenyl]-methanol

Methyl 2-fluoro-5-nitro-benzoate

A solution of 2-fluoro-5-nitro-benzoic acid (3.702 g, 20 mmol) inanhydrous methanol (10.00 mL) was treated with 98% sulphuric acid andthe solution was heated to reflux for 4 hours. The solvent was removedunder vacuum and the residue was dissolved in ethyl acetate (50 mL) Thesolution was washed with saturated aqueous sodium bicarbonate (3×10 mL),brine until neutrality and then water, and dried over anhydrous sodiumsulphate. The solvent was removed under vacuum to afford a thick oilthat started to crystallize. After adding n-hexane (3 mL) the crude wasstored for 2 days in the fridge. The crystalline compound was filteredand washed with n-hexane to yield 3.147 g of the pure compound.

By concentrating the mother liquors a second crop was obtained (390 mg)(y=89%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.94 (s, 3H) 7.69 (m, 1H) 8.55 (m, 1H)8.65 (m, 1H).

Methyl 2-(4-methyl-piperazin-1-yl)-5-nitro-benzoate

A solution of methyl 2-fluoro-5-nitro-benzoate (3.487 g, 17.511 mmol)and N-methylpiperazine (3.855 mL, 3.508 g, 35.022 mmol) in 30 mL ofanhydrous methanol was heated to reflux for 5 hours.

After removing the volatiles at reduced pressure, the crude orange oilwas treated slowly with water (about 20 mL) and stirred in an ice bathfor 1 hour. The crystalline compound formed was filtered by suctionfiltration, washed with water and dried at 40° C. under vacuum for 24hours. There were obtained 4.627 g of yellow compound (y=96%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H) 2.46 (m, 4H) 3.27 (m, 4H)3.87 (s, 3H) 7.22 (d J=9.27 Hz, 1H) 8.08 (dd J=9.27 Hz J=2.80 Hz, 1H)8.33 (d J=2.80 Hz, 1H).

2-(4-Methyl-piperazin-1-yl)-5-nitro-phenyl]methanol

A suspension of methyl 2-(4-methyl-piperazin-1-yl)-5-nitro-benzoate(1.40 g, 5.00 mmol) in anhydrous diethyl ether (60 mL) was treated withlithium borum hydride (190.5 mg, 8.75 mmol) and the formation of aprecipitate was observed. Anhydrous methanol (0.350 mL, 280.3 mg, 8.75mmol) was then added and the solution heated to reflux for 2 hours. Asthe reaction was not complete, further lithium borum hydride (190.5 mg)and methanol (0.350 mL) were added twice every 4 hours.

After cooling in ice bath, the reaction mixture was treated with water,with 1N HCl (6 mL) and stirred at room temperature for 15 minutes. Thesolution was then basified to pH 11 by 1N sodium hydroxide and extractedwith dichloromethane; the organic extracts were washed with brine andwith water and dried over anhydrous sodium sulphate. The solvent wasevaporated to dryness to afford 1,35 g of a brownish solid that waspurified by flash chromatography on silica gel (eluantdichloromethane/methanol 95:5) to yield 1,10 g of desired compound(y=87%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28 (s, 3H) 2.52 (m, 4H) 3.03 (m, 4H)4.54 (m, 2H) 5.53 (t, 1H) 7.17 (d J=8.90 Hz, 1H) 8.08 (dd J=8.90 HzJ=2.92 Hz, 1H) 8.33 (d J=2.92 Hz, 1H).

5-Amino-2-(4-methyl-piperazin-1-yl)-phenyl]methanol

To a solution of crude[2-(4-Methyl-piperazin-1-yl)-5-nitro-phenyl]-methanol (437 mg, 1.74mmol) in methanol (1.5 mL), ammonium chloride (NH₄Cl) (465 mg), water(4.9 mL) and Fe powder (290 mg) were added and the mixture was heated at100° C. for 3 hours.

The reaction mixture was filtered and the black precipitate washed withMeOH/water 1:1 (10 mL) Methanol was removed under vacuum and theremaining water was basified with sodium carbonate (Na₂CO₃) andextracted with ethyl acetate (5×20 mL) The organic extracts were washedwith brine (2×10 mL) and with water (2×5 mL) and dried over anhydroussodium sulphate. After evaporation, the resultant crude orange solid waspurified by flash chromatography on silica gel (eluantdichloromethane/methanol/triethylamine 90:10:0.1) to yield 357 mg ofpure title compound (y=92%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H) 2.52 (m, 4H) 2.73 (m, 4H)4.48 (m, 2H) 4.75 (bs, 2H) 4.95 (t, 1H) 6.43 (dd J=8.42 Hz J=2.68 Hz,1H) 6.67 (d J=2.68 Hz, 1H) 6.80 (d J=8.42 Hz, 1H).

Example 68 1-(4-Methyl-piperazine-1-carbonyl)-piperidin-4-onehydrochloride

To a suspension of 4-methylpiperazine-1-carbonyl chloride hydrochloride(19.9 g 0.1 mol) and piperidone monohydrate hydrochloride (15.3 g 0.1mol), in 200 mL of dichloromethane, dry triethylamine (45 mL, 0.33 mol)was added dropwise. The mixture was stirred for 2 hours. The organicphase was washed with brine (2×20 mL) and dried over sodium sulfate.After filtration, the solvent was evaporated in vacuo and the crudeproduct was dissolved in EtOH (50 mL) and diethylether (100 mL) andtreated with HCl 4N in dioxane (25 mL). After 1 hour, the precipitatewas filtered and dried in oven to give 13 g (yield 50%) of the titlecompound.

1H NMR (400 MHz, DMSO-D6) δ ppm 2.40 (t, J=6.16 Hz, 4H) 2.81 (s, 3H)3.00-3.11 (m, 2H) 3.12-3.23 (m, 2H) 3.28-3.42 (m, 2H) 3.51 (t, J=6.16Hz, 4H) 3.73 (d, J=14.27 Hz, 2H) 10.12 (s, 1H)

Example 69 1-acetyl-4-hydrazinopiperidine hydrochloride

Step 1: N′-(1-acetylpiperidin-4-ylidene)benzohydrazide

20 g (0.142 mol) of 1-acetyl-4-piperidone were dissolved in 400 mL ofabsolute ethanol and 21.2 g (0.156 mol) of benzoylhydrazine were added.The resulting solution was refluxed for 6 hours under stirring. Thesolvent was then removed in vacuo and the residue partitioned betweendichloromethane and water. The organic layer was dried over sodiumsulfate and evaporated to dryness. The residue was triturated withdiethylether and 30 g (83% yield) of the title compound were collectedby filtration.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (s, 3H) 2.43-2.62 (m, 4H) 3.45-3.74(m, 4H) 7.51 (m, 3H) 7.84 (m, 2H) 10.7 (bs, 1H).

Step 2: N′-(1-acetylpiperidin-4-yl)benzohydrazide

30 g (0.12 mol) of N′-(1-acetylpiperidin-4-ylidene)benzohydrazide weredissolved in 500 mL of glacial acetic acid and 1 g of PtO₂ were added.The mixture was hydrogenated at 40 psi for 12 hours at room temperature.The catalyst was then filtered on celite and the filtrate evaporated invacuo. The residue was redissolved with dichloromethane and washed withaqueous NaHCO₃. The solvent was dried over sodium sulfate and removedunder reduced pressure to give, after trituration with diethylether,28.6 g (92% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (m, 2H) 1.81 (m, 2H) 2.00 (s, 3H)3.75 (m, 2H) 4.10 (m, 2H) 4.19 (s, 1H) 7.49-7.51 (m, 3H) 7.84 (m, 2H)10.01 (s, 1H).

Step 3: di-tert-butyl1-(1-acetylpiperidin-4-yl)-2-benzoylhydrazine-1,2-dicarboxylate

To a solution of 28.6 g (0.11 mol) ofN′-(1-acetylpiperidin-4-yl)benzohydrazide in 700 mL of acetonitrile,53.19 g (0.44 mol) of 4-dimethylaminopyridine (DMAP) and 77.2 g (0.35mol) of di-tert-butyldicarbonate were added. The mixture was stirredovernight, the solvent removed and the residue taken up withdichoromethane and washed with aqueous KHSO₄ to remove DMAP. The organiclayer was dried over sodium sulfate and evaporated to give 45 g of thetitle compound as an oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 and 1.40 (2s, 18H) 1.97 (s, 3H)4.28 (m, 1H) 7.51-7.53 (m, 4H).

Step 4: di-tert-butyl1-(1-acetylpiperidin-4-yl)hydrazine-1,2-dicarboxylate

45 g (0.1 mol) of di-tert-butyl1-(1-acetylpiperidin-4-yl)-2-benzoylhydrazine-1,2-dicarboxylate weredissolved in 1 L of tetrahydrofuran and a solution of 5.8 g (0.14 mol)of lithium hydroxide monohydrate in 1 L of water were added. The mixturewas stirred at room temperature for 16 hours, the tetrahydrofuranremoved in vacuo and the aqueous layer extracted several times withdichloromethane. The organic phase was dried over sodium sulfate andevaporated to dryness, giving 32 g (84% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 and 1.42 (2s, 18H) 1.99 (s, 3H)4.09 (m, 1H) 2.52 and 3.05/2m, 4H) 3.95 and 4.41 (2m, 4H) 8.81 (bs, 1H).

Step 5: 1-acetyl-4-hydrazinopiperidine hydrochloride

32 g (0.09 mol) of di-tert-butyl1-(1-acetylpiperidin-4-yl)hydrazine-1,2-dicarboxylate were dissolved in300 mL of methanol and 30 mL of HCl 4 M in dioxane were added. Themixture was stirred at room temperature overnight. The solvent was thenevaporated and the residue crystallized from ethanol, giving 14 g (77%yield) of the title compound.

Example 70 (1S)-1-methyl-2-morpholin-4-yl-1-phenylethylaminedihydrochloride

Step 1. N-(tert-butoxycarbonyl)-2-phenyl-D-alanine

To a suspension of 500 mg of 2-phenyl-D-alanine (3.02 mmol) andtrimethylammonium hydroxide (aqueous solution 10%, 2.8 mL, 3.02 mmol) in15 mL of acetonitrile, diterbutylcarbonate (1.047 g, 4.8 mmol) was addedand the mixture was stirred at room temperature for 2 days. The solventwas then removed under vacuo, the residue was dissolved in water andwashed with diethylether. The aqueous layer was acidified to pH=3-4 withcitric acid and the product was extracted with ethyl acetate (3×20 mL)The combined organic phase was washed with water, dried over Na₂SO₄ andevaporated. The title product was recovered as white solid (630 mg,yield 78%).

Step 2.N-(tert-butoxycarbonyl)-(1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylamine

630 mg (2.374 mmol) of N-(tert-butoxycarbonyl)-2-phenyl-D-alanine weredissolved in 20 mL of dry DMF andO-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluorborate (TBTU,1.37 g, 4.27 mmol), morpholine (0.412 mL, 4.73 mmol) anddiisopropylethylamine (1.63 mL, 9.5 mol) were added. The mixture wasstirred at room temperature for 1 hour, then the solvent was removed andthe residue dissolved with dichloromethane. The solution was washed withsaturated NaHCO₃, brine, water and dried over Na₂SO₄. 700 mg of thetitle compound were recovered (88% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (s, 9H) 1.65 (s, 3H) 3.33 (m, 8H)7.35 (m, 6H).

Step 3. (1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylaminehydrochloride

A solution of 630 mg (1.884 mmol) ofN-(tert-butoxycarbonyl)-(1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylaminein 20 mL of dioxane was treated with 2.5 mL of HCl 4N in dioxaneovernight. The solvent was removed under vacuo and the solid wastriturated with diethylether yielding 560 mg of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.94 (s, 3H) 3.35 (m, 8H) 7.51 (m, 5H)8.52 (bs, 3H).

Step 4. (1S)-1-methyl-2-morpholin-4-yl-1-phenylethylaminedihydrochloride

Under an argon atmosphere 412 mg of(1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylamine hydrochloride(1.522 mol) were dissolved in 30 mL of dry THF. A 2 M solution of boranedimethylsulfide (4.4 mL, 5.78 mmol) was added dropwise at 0° C. and themixture stirred for 10 minutes at 0° C. and then allowed to reach roomtemperature (gas evolution). After 4 hours the reaction was quenchedwith methanol (added very carefully) and diluted with methanol wheneffervescence ceased. THF was removed under vacuo and the methanolicsolution was heated at 60° C. for 30 minutes. The solvent was at lastcompletely removed recovering 330 mg of the amine that was subsequentlydissolved in 15 mL of dioxane and treated with 1.35 mL of HCl 4 N indioxane. After 1 hour the solvent was evaporated and the product wastriturated with diethylether to yield 350 mg of the expected salt.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66 (s, 3H) 2.52 (m, 6H) 3.57 (m, 4H)7.51 (m, 5H) 8.53 (s, 3H).

Example 71 (1S)-2-morpholin-4-yl-2-oxo-1-phenylethylamine hydrochloride

Step 1.N-(tert-butoxycarbonyl)-(1S)-2-morpholin-4-yl-2-oxo-1-phenylethylamine

1 g (3.98 mmol) of Boc-L-phenylglicine was dissolved in 18 mL of dry DMFand 0-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoborate(TBTU, 1.92 g, 5.97 mmol), morpholine (0.555 mL, 6.37 mmol) anddiisopropylethylamine (2.72 mL, 15.92 mol) were added. The mixture wasstirred at room temperature for 1 hour, then the solvent was removed andthe residue dissolved with dichloromethane. The solution was washed withsaturated NaHCO₃, brine, water and dried over Na₂SO₄. 1.327 g of thetitle compound were recovered.

Step 2. (1S)-2-morpholin-4-yl-2-oxo-1-phenylethylamine hydrochloride

1.327 g ofN-(tert-butoxycarbonyl)-(1S)-2-morpholin-4-yl-2-oxo-1-phenylethylaminewas dissolved in 15 mL of dioxane and treated with 3.5 mL of HCl 4 M indioxane overnight. The solvent was removed and the solid was trituratedwith diethylether yielding 920 mg of the product (yield 90%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.13 (m, 4H) 3.54 (m, 4H) 5.58 (m, 1H)7.50 (s, 5H) 8.58 (s, 3H).

What is claimed is:
 1. A compound of formula (I),

wherein R is

X is —NR′—, wherein R′ is hydrogen; R₁ is methyl; R₂ is NR″R′″, whereinR″ is methyl and R′″ is hydrogen; A is —CH₂—C(CH₃)₂— or —C(CH₃)₂—CH₂—;or a pharmaceutically acceptable salt thereof.
 2. A product or kitcomprising a therapeutically effective amount of a compound of claim 1,and at least one pharmaceutically acceptable excipient, carrier ordiluent, and one or more chemotherapeutic agents, as a combinedpreparation for simultaneous, separate or sequential use.
 3. Apharmaceutical composition, comprising a compound of claim 1 and atleast one pharmaceutically acceptable excipient, carrier, or diluent. 4.The compound:

or a pharmaceutically acceptable salt thereof.
 5. The compound:


6. A pharmaceutically acceptable salt of the compound of claim
 4. 7. Ahydrochloride salt of the compound of claim
 4. 8. The tri-hydrochloridesalt of the compound of claim
 4. 9. A product or kit comprising atherapeutically effective amount of a compound of claim 4, and at leastone pharmaceutically acceptable excipient, carrier or diluent, and oneor more chemotherapeutic agents, as a combined preparation forsimultaneous, separate or sequential use.
 10. A pharmaceuticalcomposition, comprising a compound of claim 4 and at least onepharmaceutically acceptable excipient, carrier, or diluent.